Purpose: Human tuberculosis (TB) is a shared global health problem that causes nearly 1.5 million deaths per year worldwide. Although current TB chemotherapy can cure drug sensitive TB (DS-TB), it needs to be administered as a cocktail of antibiotics for eight months. This lengthy therapy results in low patient compliance and is the main reason attributable to the emergence of multidrug-resistant (MDR) and, recently, to extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb). One approach presented here to possibly ease TB therapy and shorten treatment time is to combine anti-TB multidrug therapy with inhalational TB therapy of the newly developed anti-TB drug specinamide-1599. Recent results suggest that spectinamide-1599 is a great candidate for developing a new inhalational therapy to treat DS-TB and MDR-XDR-TB: when delivered directly to the lungs it provides higher exposure and anti-bacterial activity in the lungs than when administered at equivalent doses by a subcutaneous route. Additionally, moving to an inhaled therapy removes the intravenous administration requirement for spectinamide-1599 which may improve patient adherence to TB therapy. The aim of this work was to characterize dry powder formulations of spectinamide-1599 toward inhaled TB treatment.
Methods: Dry powder particles of spectinamide-1599 with and without the excipient l-leucine were spray dried using a Buchi-B290 with a high efficiency cyclone. 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 using custom dosators was also examined. Finally, the effect of individual dry powder inhaler (DPI) pressure drop and resistance to flow on the aerodynamic properties of spectinamide-1599:leucine powders was analyzed.
Results: Dry powders in the respirable size range (<5 µm) were successfully manufactured and characterized. Additionally, a decrease in density and increase in dispersibility as well as delivered dose reproducibility was seen as the leucine content was increased.
Conclusion: Spray dried formulations of dry powder spectinamide-1599:leucine 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 mice. The discovery of spectinamide-1599 aerosols for inhaled therapy is expected to add to the toolbox of options available to the growing research concerning alternatives for TB treatment.
Jennifer Arab– Colorado State University, Fort Collins, Colorado
Amanda Walz– Colorado State University, Fort Collins, Colorado
Mercedes Gonzalez-Juarrero– Colorado State University, Fort Collins, Colorado
Bernd Meibohm– Professor and Associate Dean, University of Tennessee Health Science Center, Memphis, Tennessee
Miriam Braunstein– University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Anthony Hickey– RTI International, Durham, North Carolina