Highly respirable dry powder inhalable formulation of voriconazole with enhanced pulmonary bioavailability

ABSTRACT

Objective: To develop and characterize a highly respirable dry powder inhalable formulation of voriconazole (VRZ).

Methods: Powders were prepared by spray drying aqueous/alcohol solutions. Formulations were characterized in terms of particle size, morphology, thermal, moisture responses and aerosolization performance. Optimized powder was deposited onto an air-interface Calu-3 model to assess their uptake across Calu-3 lung epithelia. Optimized formulation was evaluated for stability (drug content and aerosol performance) for 3 months. Additionally, Calu-3 cell viability, lung bioavailability and tissue distribution of optimized formulation were evaluated.

Results: Particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy. Optimized formulation showed irregular morphology, crystalline nature, low moisture sensitivity and was stable for 3 months at room temperature. Leucine did not alter the transport kinetics of VRZ, as evaluated by air-interface Calu-3 model. Formulation was non-cytotoxic to pulmonary epithelial cells. Moreover, lung bioavailability and tissue distribution studies in murine model clearly showed that VRZ dry powder inhalable formulation has potential to enhance therapeutic efficacy at the pulmonary infection site whilst minimizing systemic exposure and related toxicity.

Conclusion: This study supports the potential of inhaled dry powder VRZ for the treatment of fungal infections.

KEYWORDS:

• Leucine
• lung bioavailability
• pulmonary delivery
• spray drying
• storage stability
• voriconazole (VRZ)

Acknowledgments

Authors are grateful to the Director, NIPER and Woolcock Institute of Medical Research, for providing the necessary facilities for carrying the current research. Authors also thank Prof. Dr. H.J Butt for the kind support at the Max Planck Institute for Polymer Research, Mainz, Germany.

ORCID

Sumit Arora http://orcid.org/0000-0001-8860-667X

Daniela Traini http://orcid.org/0000-0002-7173-017X