Systematic development of novel drug delivery systems of Voriconazole and Ceftazidime for efficient treatment of pulmonary infections

Abstract

The work encompasses systematic development of nano-embedded microdroplets of voriconazole (VRC) and ceftazidime (CFZ) for pulmonary targeting. Initially, analytical method for the quantitative estimation of both the drugs was developed employing HPLC, following the principles of Analytical Quality by Design (AQbD). Further, bioanalytical method was established to carry out the in vivo pharmacokinetic studies on the optimized formulations. Varied nanoparticulate systems like, lipid nanovesicles, lipid-polymer hybrid nanoparticles of VRC and lipidic nanoparticles of CFZ, were developed, as per the QbD-approach. The patient-centric QTPP was defined, and various CQAs were identified based on the prior knowledge and literature reports. Ishikawa fish-bone flow chart was construed to envision the cause-effect relationship(s) through risk assessment exercises, like REM and FMEA. Subsequently, factor screening studies were conducted, employing apt experimental designs (e.g., TgD, FFD, etc.,) and systemically optimized using response surface designs (e.g., CCD, BBD, etc.,) for the chosen CQAs. The aerodynamic performance, was analyzed employing Spraytec laser diffraction and Next-generation impactor. In vitro interaction of formulations with natural (i.e., A549 cellular lipids) and synthetic (i.e., DPPC) lipid monolayers mimicking pulmonary surfactant monolayer was explored for investigating their surface-active potential and stability vis-à-vis the respective pure drug(s). Further, the optimized formulations were tested on lung epithelial cells for their safety and uptake potential. In vivo studies carried out in mice employing an in-house designed nose-only inhalation chamber indicated marked improvement in biopharmaceutical attributes in lungs vis-à-vis pure drugs. newline