A Triple Combination Anti-Tubercular Dry Powder Formulation for Treating Both Drug Susceptible and Multidrug Resistant Tuberculosis: Formulation and In Vitro Characterization
Shyamal C. Das, Claire Fan, Basanth Babu Eedara & Shubhra Sinha
School of Pharmacy, University of Otago, Adams Building, 18 Frederick Street, P.O. Box 56, Dunedin 9054, New Zealand.
Tuberculosis (TB) is a leading cause of death. Current pharmacotherapeutic regimens for TB require high oral and parenteral doses of multiple drugs for long periods (6-24 months), leading to significant adverse effects. PA824-moxifloxacin-pyrazinamide combination showed efficacy superior to the current standard regimen of isoniazid-rifampicin-pyrazinamide-ethambutol. Moreover, this combination has activity against both drug-susceptible and multi-drug resistant TB (MDR-TB) and gives rise to fewer drug–drug interactions. The aim of this study was to develop a safe, well tolerated, stable dry powder formulation for delivery of high doses of drug to the lung for the treatment of both drug-susceptible and MDR-TB. The triple anti-tubercular dry powder formulations of pyrazinamide, moxifloxacin and PA-824 at 8:2:1 weight ratios were produced with and without L-leucine (20% w/v) by spray drying. The triple combination powder containing L-leucine produced hollow, spherical dimpled particles (<5 μm) and showed good aerosolization behaviour with a fine particle fraction of 70%. The X-ray photoelectron spectroscopy revealed the predominant surface composition of L-leucine. Further, X-ray diffraction study confirmed the amorphous nature of moxifloxacin and PA-824, crystalline nature of pyrazinamide with polymorphic transformation after spray drying process. The dose response cytotoxicity results showed the triple combination powder was safe and nontoxic in both A549 and Calu-3 cell lines. This powder can be an excellent candidate for clinical study for direct delivery of drugs to the lung to treat tuberculosis with potential to improve treatment efficacy with less systemic side effects.