Erlotinib-Fisetin-SBE-β-CD Complex for Pulmonary Delivery as an Improved Treatment for Non-small Cell Lung Cancer (NSCLC)
Noratiqah Mohtar1,2, Kevin M. G. Taylor1 & Satyanarayana Somavarapu1
1Department of Pharmaceutics, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom
2School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Pulau Pinang, Malaysia
Combination of anticancer agents with flavonoids has attracted wide attention for providing synergistic activity or to reverse acquired drug resistant in cancer treatment. This study has investigated erlotinib (a tyrosine kinase inhibitor) and fisetin (a flavonoid) against the human lung adenocarcinoma cell line (A549). A molar ratio of erlotinib: fisetin (1:2), with a combination index value of 0.42, was the most synergistic according to the median-effect principle method. A phase-solubility study of the combination in hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD) showed a greater solubilization of both drugs in the latter system. An erlotinib-fisetin-SBE-β-CD complex was prepared using 50 %v/v ethanol in water and the solution was lyophilized to improve the stability of the complex. Redispersion of the dried complex in 3-times higher concentration than the original solution showed 85.34 ± 2.31 and 100.44 ± 4.33 % solubilization of erlotinib and fisetin, respectively, after 1 h. The redispersed solution showed sufficient solubility and stability to be delivered as a nebulized solution in the Next Generation Impactor (NGI), giving a fine particle fraction (FPF) of ~70% and mass median aerodynamic diameter (MMAD) of ~5.3 µm for both drugs. In conclusion, a nebulized preparation of erlotinib-fisetin-SBE-β-CD complex improved the solubility and capability for both drugs to be delivered to the deep lung region as a potential local therapy in non-small cell lung cancer (NSCLC).