Systematic development and characterization of inhalable dry powder containing Polymeric Lipid Hybrid Nanocarriers co-loaded with ABCB1 shRNA and docetaxel using QbD approach

Abstract The main objective of this research work was to extend the principles of the Quality by Design approach in optimization and development of dry powder inhalers containing hybrid nanocarriers for effective treatment of multidrug-resistant lung cancer. Two statistical designs were used to justify the feasibility and advantages of the Qbd approach for the development of PLHNCs (Polymeric Lipid Hybrid Nanocarriers). The particle size and encapsulation efficiency were selected as quality target profile. Plackett-Burman design (PBD) was used as the first design to evaluate 7 high-risk variables that have significant effect on the characteristics of PLHNCs. Among the 7 high-risk variables, 3 variables (i.e., concentration of polymer, lipid to polymer ratio and drug input) had a significant effect on encapsulation efficiency of PLHNCs. Box-Behnken design (BBD) was employed as the second statistical design to fully elucidate the formulation development parameters. It was found that the optimized range for the parameters showed promising results to achieve a quality target profile. Further, the optimized PLHNCs formulation was subjected to lyophilization using various cryoprotectants to increase drug retention and dry powder inhaler was developed using different grades of modified lactose to achieve better aerodymic properties. The PLHNCs developed using PBD and BBD showed significant increase in Docetaxel encapsulation along with high shRNA pDNA complexation. The developed product had an higher fine particle fraction (68.3 ± 2.5%) along with high drug retention (98.3 ± 3.1%) which showed how efficiently the developed dry powder of PLHNCs would be able to target the respiratory zone of the lungs.