Abstract
Gefitinib is a tyrosine kinase inhibitor that is intended for oral administration yet suffers poor bioavailability along with undesirable side effects. To enhance its solubility and allow colon targeting, gefitinib (ZD) and blends of different ratios of polymers (ternary dispersion) were prepared in organic solution, and solid dispersions were generated employing the spray drying (SD) technique. The methylmethacrylate polymer Eudragit S 100 was incorporated for colon targeting; polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) were utilised to improve the solubility of ZD. SEM, DSC, XRPD, FT-IR, dissolution and cytotoxicity studies were undertaken to characterise and evaluate the developed formulations. SEM images revealed that the rod-shaped crystals of ZD were transformed into collapsed spheres with smaller particle size in the spray-dried particles. DSC, FTIR and XRPD studies showed that ZD loaded in the spray-dried dispersions was amorphous. ZD dissolution and release studies revealed that while a significant (P < 0.05) increase in the ZD dissolution and release was observed from HPMC-based solid dispersion at pH 7.2 (up to 95% in 15 h), practically no drug was released at pH 1.2 and pH 6.5. Furthermore, the HPMC-based solid dispersions displayed enhanced mucoadhesive properties compared with PVP-based ones. Interestingly, cell viability studies using the neutral red assay showed that PVP and HPMC-based solid dispersions had no additional inhibitory effect on Caco-2 cell line compared to the pure drug.
Highlights
Gefitinib (ZD) is a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that inhibits signal pathways involved in the growth of solid tumour and metastasis
Thermograms for PVP, hydroxypropyl methyl cellulose (HPMC) and Eudragit S 100 show the lack of melting peak which confirm they are in amorphous forms
All ternary dispersions have shown a single glass transition (Tg) with the lack of an endothermic event. This indicates the presence of ZDPS; and gefitinib (ZD) in the amorphous state and formation of homogeneous dispersions of ZD within these polymers. These results agree with the X-ray Diffractometry (XRD) data, which indicate that ZD was amorphous in all of the solid dispersion formulations
Summary
Gefitinib (ZD) is a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that inhibits signal pathways involved in the growth of solid tumour and metastasis. Colon-targeted delivery has gained much popularity for treating local diseases of the colon such as ulcerative colitis and colon cancer. These targeted dosage forms can provide high local drug concentration with minimal systemic side effects. One of the most widely used approaches for developing successful colon-targeted drug delivery is coating drug particles with pH-sensitive polymers (such as Eudragit S100). Such a strategy would prevent premature and undesirable rupture of the polymeric membrane in upper parts of
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