Erlotinib complexation with randomly methylated β-cyclodextrin improves drug solubility, intestinal permeability, and therapeutic efficacy in non-small cell lung cancer

Abstract

The purpose of this study was to investigate the impact of anticancer drug erlotinib-randomly methylated-β-cyclodextrin complex (ERL-RAMEB CD) on drug solubility and dissolution rate. Phase solubility study showed erlotinib displayed maximum solubility in RAMEB CD solution and the stability constant (K_c) was calculated to be 370 ± 16 M⁻¹. The optimal formulation was obtained with ERL-RAMEB CD in a 1:1 molar ratio using the co-lyophilization technique. Differential scanning calorimetry (DSC) and Scanning electron microscopy (SEM) verified the inclusion of complex formation. In vitro dissolution study confirmed ERL-RAMEB CD as a favorable approach to increase drug dissolution with a 1.5-fold increase than free ERL at 1 h. An improved dissolution with ∼88.4% drug release at 1 h was observed, in comparison with Erlotinib with ∼58.7% release in 45 min. The in vitro cytotoxicity results indicated that the ERL-RAMEB CD inclusion complex reduced cell viability than free erlotinib. Caco-2 cell uptake that is indicative of drug intestinal permeability resulted in a 5-fold higher uptake of ERL-RAMEB CD inclusion complex than the ERL solution. Hence, ERL-RAMEB CD complexation displays a strong potential to increase dissolution and permeability of erlotinib leading eventually to enhanced oral bioavailability.

Keywords:

• Erlotinib
• cyclodextrin
• randomly methylated β-cyclodextrin
• inclusion complex
• solubility
• oral drug delivery
• lung cancer

Acknowledgments

Erlotinib hydrochloride was a kind gift of Nobel Pharmaceuticals, Turkey purchased from Hetero Labs (Gaddapotharam, India).

Disclosure statement

The authors declare no conflicts of interest.