Fabrication of ß-cyclodextrin-mediated single bimolecular inclusion complex: characterization, molecular docking, in-vitro release and bioavailability studies for gefitinib and simvastatin conjugate.

OBJECTIVES: Introduction of multiple molecules in a single inclusion complex, albeit cheaper, lacks conclusive attempts in earlier drug delivery reports. This manuscript emphasizes simultaneous incorporation of two anticancer drugs, gefitinib (G) and simvastatin (S), in a single molecule of ß-cyclodextrin for the first time to achieve effective drug delivery. METHODS: The inclusion complex (GSBCD) was prepared by cosolvent evaporation technique using ß-cyclodextrin (BCD) as carrier. Characterization of GSBDC was performed by Fourier transform infrared spectroscopy, COSY, differential scanning calorimetry, X-ray diffraction and dynamic light scattering analyses, which were ascribed to the complex formation inside BCD cavity, micronization of drugs and conversion to amorphous state. KEY FINDINGS: The complex revealed entrapment of G and S in 3 ± 0.48: 2 ± 0.19 molar ratio and showed more than 3.5 and 10 fold increase in drug release in in vitro and in vivo, respectively. Docking and COSY studies revealed molecular alignment into BCD central cavity that been achieved via hydrogen bonding between certain groups of the ligands (G and S) and the polar heads of BCD. Partial incorporation of the molecular backbone inside inclusion complex suggests superficial contact with the solvent indicating slow steady release kinetics. CONCLUSIONS: This approach of forming inclusion complex with multiple molecules within a single cavity can be a landmark for further studies in drug delivery.