Ibrutinib amorphous solid dispersions with enhanced dissolution at colonic pH for the localized treatment of colorectal cancer

Abstract

Colorectal cancer (CRC) is the second most leading cause of cancer-related deaths worldwide. Ibrutinib (IBR), the first in class bruton tyrosine kinase (BTK) inhibitor has promising anticancer activity. In this study, we aimed to develop a hot melt extrusion based amorphous solid dispersions (ASD) of IBR with enhanced dissolution at colonic pH and assess the anticancer activity against colon cancer cell lines. Since colonic pH is higher in CRC patients compared to healthy individuals, Eudragit® FS100 was used as pH dependent polymeric matrix for colon enabled release of IBR. Poloxamer 407, TPGS and poly(2-ethyl-2-oxazoline) were screened as plasticizer and solubilizer to improve the processability and solubility. Solid state characterization and filament appearance confirmed that IBR was molecularly dispersed within FS100 + TPGS matrix. In-vitro drug release of ASD showed > 96% drug release within 6 h at colonic pH with no precipitation for 12 h. Contrary, crystalline IBR showed negligible release. ASD with TPGS showed significantly higher anticancer activity in 2D and multicellular 3D spheroids of colon carcinoma cell lines (HT-29 and HT-116). The outcomes of this research suggested that ASD with a pH dependent polymer is a promising strategy to improve solubility and an effective approach in colorectal cancer targeting.

Keywords: Amorphous Solid Dispersion; Bruton’s tyrosine kinase; Colon Cancer; Colonic targeted drug delivery system; Eudragit® FS100; Hot Melt Extrusion.