Concurrent oral delivery of non-oncology drugs through solid self-emulsifying system for repurposing in hepatocellular carcinoma

Abstract

Objective Present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs. Significance The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations. Methods The non-oncology drugs (alone and in combinations) were screened in vitro for anticancer effect (against HepG2 cells) using (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as Ketoconazole (KCZ), Disulfiram (DSR), Tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin® US2 (adsorbent carrier) was developed and characterized. Results The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 picomoles), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The Docetaxel (DTX) inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm) and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower in vivo toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss). Conclusion The current study revealed a non-oncology drug combination effective against hepatocellular carcinoma. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer.