QbD assisted development of inhalable spray-dried erlotinib procubosomal system for the effective management of non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) is the most common and leading cause of cancer deaths worldwide. Erlotinib (ERL), an epidermal growth factor receptor (EGFR) kinase inhibitor, has been used as a primary prescription for the effective treatment of metastatic NSCLC. However, it has poor aqueous solubility, extensive first-pass metabolism, oral administration-related toxicities, and inconveniences for cancer patients with gastrointestinal tract (GIT) disorders that limit its therapeutic potential. To resolve the above challenges, inhalable ERL-loaded spray-dried procubosomal powder (ERL-SDPP) was developed employing a Box-Behnken design that exhibit impressive characteristics including a device removal efficiency (DRE) of 84.7 ± 2.37 %, aerosolization efficiency (AE) of 18.1 ± 0.75, fine particle fraction (FPFTSI) of 33.7 ± 1.28 %, drug content (DC) of 93.6 ± 3.9 %, and a reconstituted cubosome size (PS) of 453.87 ± 14.65 nm. During in-vitro characterization, the optimized inhalable ERL-SDPP formulation was found to have 96.2 ± 3.98 % entrapment efficiency, −28.6 ± 1.38 mV zeta potential, and 3.29 ± 0.53 μm mass median aerodynamic diameter (MMAD). In-vitro drug release studies revealed sustained release behavior of ERL from ERL-SDPP lasting up to 36 h, demonstrating the increased dissolution profile and stability of ERL-SDPP in simulated lung fluids compared to pure ERL. In-vitro cytotoxicity studies utilizing A549 cell lines uncovered the greater potential of ERL-SDPP formulation, with a ∼1.5-fold reduction in IC50 compared to pure ERL, after 24 h treatment. In-vivo pharmacokinetic parameters revealed that inhalable ERL-SDPP exhibited a 1.76-fold and 6.25-fold higher AUC than oral and intravenous administered ERL, respectively. Organ distribution studies confirmed enhanced retention and accumulation of ERL in lungs after administration of inhalable ERL-SDPP compared to oral ERL, thereby reducing the dose and related systemic toxicities. Thus, the developed inhalable ERL-SDPP has shown promise to improve therapeutic potential against NSCLC through a site-specific sustained drug delivery system as it requires lower doses and limits systemic side effects.