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Engineering Voriconazle Inhalable Powder Formulations for the Treatment of Respiratory Fungal Infections

Arora S, Haghi M, Young PM, Kappl M, Traini D, Jain S.

RDD Asia 2016. Volume , 2016: 101-110.

Abstract:

The present research explored the potential of voriconazole (VRZ) as inhaled therapy for the treatment of invasive pulmonary aspergillosis (IPA). Two formulation approaches were explored. The first involved co-spray drying VRZ and L-leucine (LEU) to form a high dispersible dry powder of VRZ (VRZ_LEU), while in the second part of the project, VRZ and polylactide (PLA) was spray dried to obtain inhalable sustained release VRZ-loaded PLA microparticles (VLM). Both the formulations were found to be suitable for inhalation therapy based on their particle size and aerosolization performance. VRZ_LEU and VLM exhibited mass median aerodynamic diameters of 3.79 ± 0.02 μm and 3.68 ± 0.05 μm, respectively. VRZ_LEU exhibited irregular morphology and a crystalline nature as determined by scanning electron microscopy and thermal analysis. VLM, on the other hand, was found to exhibit spherical morphology and amorphous behavior. VRZ_LEU was found to be stable for three months in terms of drug content and aerosol performance when stored at room temperature (25°C and 60% RH), while optimum performance of VLM could only be ensured if it was stored under refrigerated conditions (2-8°C at less than 25% RH). In vitro air-interface Calu-3 deposition studies indicated that PLA was able to sustain VRZ release from the matrix for over 48 hours. Both formulations were found to be non-toxic using Calu-3 cell viability assays. Lastly, in vivo studies in a murine model revealed that VRZ_LEU and VLM delivered as aerosol can maintain VRZ concentrations markedly above the minimum inhibi- tory concentration (1 μg/ml) of Aspergillus spp. in lung tissue for nearly 8 hours, and 24 hours after initial dosing, respectively. Both the formulations exhibited enhanced lung exposure while simultaneously reducing systemic exposure of VRZ in comparison with the intravenous administration of VRZ.