Afatinib liposomal dry powder inhaler: Targeted pulmonary delivery of EGFR inhibitor for the management of lung cancer

Abstract

The present research work aims to prepare a liposomal dry powder inhaler (LDPI) of afatinib dimaleate for the treatment of non-small cell lung cancer through pulmonary delivery. The influence of formulation independent variables, lipid concentration (X1, mol%) and organic phase (X2, mL), on dependent variables, entrapment efficiency (%) and particle size (nm), were investigated using a three-level factorial design. The optimized drug encapsulated PEGylated liposomal batch of 2 mL prepared by ethanol injection method was further scaled up to 25 mL, to enable lyophilization used to convert liposomal dispersion into LDPI. Scale-up batch of liposomes was found to have an average particle size of 181.2 ± 5.0 nm, % entrapment efficiency of 75.31 ± 2.70%, and zeta potential of 9.65 ± 0.31 mV. LDPI manufactured with trehalose as a cryoprotectant and l-leucine as an antiadherent offered porous particles with smooth morphologies that improved aerodynamic efficiency. The prepared LDPI formulation exhibited 9.639 ± 1.369 μm of particle size distribution, 72.56 ± 1.04% drug content, and good flow properties. In vitro lung deposition study implied that particles could reach the deeper region of the lung with more than 85% dose emission from an inhaler device. In vitro drug release study revealed that the drug release profile in pH 7.4 buffer was lower than in pH 5.5 and pH 6.5 buffers, demonstrating the stability of LDPI in lung fluid. Cytotoxicity study utilizing A549 adenocarcinoma cell line uncovered the greater potential of liposomal formulation in inhibiting tumor cell growth as compared to plain drug solution. The cellular uptake across adenocarcinoma cells exhibited more intracellular uptake of fluorescein isothiocyanate (FITC) encapsulated afatinib liposomal formulation than plain FITC dye. Thus, the optimized LDPI can offer an excellent approach for managing lung cancer through site-specific delivery.