Montelukast-loaded nanostructured lipid carriers: Part II Pulmonary drug delivery and in vitro–in vivo aerosol performance

• Montelukast-NLC-DPI was prepared for pulmonary application using 3% mannitol.
• In vitro aerosol performance was evaluated using 8-stage cascade impactor.
• Optimum MMAD and FPF were achieved for MNLC-DPI at 30 and 60 L/min flow rate.
• In vivo intra-tracheal instillation study showed improved pulmokinetics.
• 12-fold increase in bioavailability and targeting factor of 11.76 was achieved.

The aim of the present study was to establish the potential of montelukast loaded nanostructured lipid carrier (MNLC) for pulmonary application. The formulated nanoparticles were evaluated in vitro for aerodynamic characterization and in vivo for pulmokinetics in Wistar rats. The in vitro cytotoxicity was performed on A549 cell line and compared with montelukast-aqueous solution. MNLC was prepared with montelukast (0.2%), Precirol ATO5 (solid lipid), and Capryol-90 (liquid lipid) in the ratio of 7:3 using melt-emulsification-homogenization method. dl-Pyrrolidonecarboxylic acid salt of l-cocyl arginine ethyl ester (CAE), a biodegradable surfactant in the concentration of 1% was used to stabilize the nanoparticles. The particle size and encapsulation efficiency (EE) were 184.6 ± 2.7 nm and >95%, respectively. MNLC-Dry powder for inhalation (DPI) was prepared by lyophilization using 3% mannitol as cryoprotectant and carrier. MNLC-DPI was evaluated for flow, crystallographic and thermal properties. Mass median diameters (MMD) and density for MNLC-DPI were found to be 15.1 ± 1.4 μm and 0.051 ± 0.002 g/cc, respectively. In vitro aerosol performance study indicated more than 95% of the emitted dose (ED) at both the flow rates studied. Mass median aerodynamic diameters (MMAD) of 3.24 ± 0.67 μm with 69.98 ± 1.9% fine particle fraction (FPF) were obtained at 30 L/min flow rate, whereas at 60 L/min MMAD and FPF were found to be 2.83 ± 0.46 μm and 90.22 ± 2.6%, respectively. In vitro cytotoxicity study on A549 cells revealed higher safety of MNLC than pure drug. The pulmonary pharmacokinetic study demonstrated improved bioavailability, longer residence of drug in the lung and targeting factor of 11.76 for MNLC as compared to montelukast-aqueous solution. Thus, the results of the study demonstrated the potential of montelukast lipidic nanoparticulate formulation to improve the efficacy with reduced toxicity leading to better performance of drug as MNLC-DPI for inhalation use.

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