Surface Modified Voriconazole Dry Powder Inhalable Formulation for the Treatment of Invasive Pulmonary Aspergillosis

Sumit Arora, Mehra Haghi, Paul M. Young, Michael Kappl, Daniela Traini, Sanyog Jain

Background: Invasive pulmonary aspergillosis (IPA) is a severe disease in immunocompromised patients with extremely high mortality rate. Voriconazole (VRZ) is a first line treatment drug for IPA, conventionally administered orally or intravenous, resulting in a plethora of drug-drug interactions and off-target toxic effects. In the present research work, we developed and characterised a highly dispersible dry powder inhalable formulation of VRZ using L-Leucine as a dispersibility enhancer. Methods: VRZ and L-Leucine in varying concentrations were dissolved in ethanol-water (70:30% v/v) and spray dried to yield inhalable dry powders. Powders were characterised in terms of particle size, morphology and aerosol performance using the low resistance RS01 dry powder device with next generation cascade impactor. Storage stability (chemical stability and aerosol performance) of the optimized formulation was evaluated for 3 months. Calu-3 sub bronchial epithelial cell line was used to study cell viability (MTS test). Finally, in vivo pharmacokinetic studies in mice were carried out to determine the lung bioavailability of the optimised formulation. Results: Dry powder comprising VRZ (8 mg/mL) and L-Leucine (2 mg/mL) was found to be suitable for inhalation therapy. Powder exhibited a volume median diameter of 2.64 ± 0.05 μm and superior aerosolisation with MMAD of 3.79 ± 0.02 μm and fine particle fraction (% aerosol < 5 μm) of 60.00 ± 0.94 %. Powder exhibited irregular morphology and demonstrated physico-chemical stability of up to 3 months at room temperature. Formulation was found to be non-cytotoxic to Calu-3 cells. Moreover, lung bioavailability in murine model showed the ability of inhaled formulation to attain higher concentration of VRZ in lungs as compared to intravenous administration. Conclusion: A highly respirable dry powder VRZ formulation was developed for the treatment of IPA.

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