A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis

Manse Kim, Claire E. Johnson, Alan A. Schmalstig, Ayano Annis, Sarah E. Wessel, Brian Horn, Amanda Schauer, Agata A. Exner, Jason E. Stout, Angela Wahl, Miriam Braunstein, J. Victor Garcia () and Martina Kovarova ()
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Manse Kim: University of North Carolina at Chapel Hill
Claire E. Johnson: University of North Carolina at Chapel Hill
Alan A. Schmalstig: University of North Carolina at Chapel Hill
Ayano Annis: University of North Carolina at Chapel Hill
Sarah E. Wessel: University of North Carolina at Chapel Hill
Brian Horn: University of North Carolina at Chapel Hill
Amanda Schauer: University of North Carolina at Chapel Hill
Agata A. Exner: Case Western Reserve University
Jason E. Stout: Duke University
Angela Wahl: University of North Carolina at Chapel Hill
Miriam Braunstein: University of North Carolina at Chapel Hill
J. Victor Garcia: University of North Carolina at Chapel Hill
Martina Kovarova: University of North Carolina at Chapel Hill

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.

Date: 2022
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DOI: 10.1038/s41467-022-32043-3

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