Purpose: With 1.5 million deaths annually from TB and increasing numbers of drug resistant TB cases (MDR, XDR), it is critical that new TB therapies be developed. Along with new drugs that work on resistant Mycobacterium tuberculosis (Mtb) strains, strategies to shorten the duration of therapy are needed to simplify treatment, improve adherence, and limit periods of transmission. The focus of this work is to evaluate inhaled pyrazinoic acid (POA) as an adjunctive therapy for TB. Inhaled POA would work on the largest category of pyrazinamide (PZA, a prodrug that is converted to its active moiety, POA) resistant Mtb strains and it also has the potential to improve the efficacy of current TB treatment regimens. We have previously shown that formulations of POA salts and esters are suitable for inhalation; our purpose here is to extend this research to POA alone and characterize the quality of the resulting aerosol.
Methods: Dry powder particles of POA were spray dried via factorial design (n=3) where atomizing gas flow, POA solution (5 mg/mL) flow rate, and inlet temperature of the spray dryer (Buchi-B290 with a high efficiency cyclone) low/high conditions were set at 473/601 L/h, 2.5/5mL/min, and 120/190 °C respectively. Percent recovery (by mass), geometric particle size (via SEM), aerodynamic particle size distribution (via laser diffraction and impaction), and unbound moisture content (via TGA) were characterized. Delivered dose reproducibility with and without excipients (L-leucine, mannitol, trehalose, and lactose) using custom dosators was also examined.
Results: Percent recovery varied widely from <5% - 70% among the samples, but in every case the microparticles exhibited geometric and aerodynamic particle sizes in the respirable range of <5 µm with varying morphologies. Thermographs were identical to pre-spray dried POA and indicated a 0% weight loss prior to ~ 150 °C implying negligible moisture content. The addition of excipients improved the dispersibility and delivered dose reproducibility of the spray dried POA.
Conclusion: Spray dried formulations of dry powder POA exhibit promising characteristics in the context of inhaled therapies. It is our goal to use these powders in efficacy/PK studies to investigate their therapeutic effect following inhalation in guinea pigs.