Risk Assessment and QbD-Based Optimization of Sorafenib Tosylate Colon Targeted Bilayer Tablet: In Vitro Characterization, In Vivo Pharmacokinetic, and In Vivo Roentgenography Studies.

The employment of site-specific administration in colon is a promising technique to improve efficacy and reduce systemic side effects of anticancer medications used in colorectal cancer. However, the physiology of the gastrointestinal tract and colonic environment limit the efficient delivery of orally administered anticancer drugs to the colon. These prerequisites can be fulfilled by a release modulated colon targeted drug delivery system (CTDDS) based on pH-dependent chronotherapeutic bilayer tablet of sorafenib tosylate (ST). Quality by design (QbD) was used to examine the risk assessment. The Box-Behnken design was used to optimize the core uncoated bilayer tablet, whereas the 2 factorial design was used to optimize the coating process. The amount of croscarmellose sodium, Eudragit RLPO, and tablet hardness all had a significant impact on disintegration time and drug release, according to the results of the core uncoated bilayer optimization. The amount of Eudragit S 100 and PEG 400 in the final coated tablet had a considerable impact on drug release. The optimized formulation demonstrated 5-h lag time, a peculiar feature of CTDDS. The pharmacokinetic studies of coated tablet in rabbits showed lower C (4.45 ± 0.40 µg/mL) and AUC (148.52 ± 3.96 h µg/mL), whereas T was substantially delayed (8.0 ± 0.57 h) compared to core uncoated tablet. The tablet remained intact until it reached the colon (> 4 h), according to the in vivo roentgenography studies. The present study revealed that a QbD approach can be useful to develop a rugged and scalable CTDDS.