Inclusion Complexation of Gefitinib with Cyclodextrins

Abstract

Gefitinib, a very slightly soluble new drug, is used in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy. This study examined the complexation of gefitinib with three selected cyclodextrins, ß-cyclodextrin (ßCD), hydroxypropyl-ß-cyclodextrin (HPßCD), and randomly methylated ß-cyclodextrin (RMßCD), with the objective of improving the solubility and dissolution of the drug. Phase solubility studies were performed with the different cyclodextrins to characterize the complexation in the liquid state. The complexation in the solid state was characterized by differential scanning calorimetry and x-ray diffraction analyses. The dissolution studies were performed using USP dissolution testing equipment and the dissolution samples were analyzed by an UV spectrophotometric assay. The solubility of gefitinib was significantly improved by all cyclodextrins (CDs) in the study. The association rate constants (Ks) calculated from the phase solubility diagrams indicate that gefitinib can form a stable inclusion complex with all three CDs. The freeze-dried formulations showed substantial increases in the dissolution of gefitinib with all three CDs compared to gefitinib alone, while the kneaded and physical mixtures showed no improvement in the dissolution. Furthermore, addition of the hydrophilic polymers polyvinyl pyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) markedly enhanced the dissolution of gefitinib from CD complexes. The gefitinib-HPßCD (1:1) complex yielded 50% dissolution in 1 hr whereas PVP or HPMC in association with the complex increased the dissolution up to 95% within 1hr. In conclusion, gefitinib can form a stable inclusion complex with all three cyclodextrins as demonstrated by the liquid and solid state complexation studies. HPßCD showed the greatest improvement in the dissolution of gefitinib followed by RMßCD and ßCD.