Quality by Design-driven Development of 5-fluorouracil Loaded Mucoadhesive Microparticulate Drug Delivery Systems for Effective Chemotherapy for Colorectal Cancer

Abstract

Aims: To enhance oral bioavailability and decrease the dosing frequency of 5-Fluorouracil Background: Cancer is one of the most dreadful diseases for which complete cures are not possible, but colorectal cancer is completely curable if diagnosed at an early stage. If diagnosed in late-stage, 5-Fluorouracil (5-FU) is mostly recommended for its effective treatment, but the challenges associated with this drug are short elimination half-life, severe side effects, as well as non-specificity. The challenges can be better addressed by fabricating microbeads using the QbD approach. To enhance the oral bioavailability of 5-FU and to target the colon for the effective treatment of colorectal cancer, the microbeads were fabricated by emulsification crosslinking method using Box-Behnken design. Objective: To target the colon for effective treatment of colorectal cancer with enhanced oral bioavailability. Methods: The microparticulate drug delivery system was fabricated by using the emulsification crosslinking method by implementing a quality design approach with risk assessment followed by characterization such as FTIR, DSC, TGA, XRD, in vitro drug release, in vitro cytotoxicity study and in vivo pharmacokinetic studies. Results: The patient-centric quality target product profile (QTPP) was set. QTPP inspired critical quality attributes (CQAs) were searched out. The critical material attributes (CMAs) and critical process parameters (CPPs) influencing CQAs were distinguished. The seventeen formulations were fabricated employing Box Behnken Design, followed by optimization using numerical and graphical optimization techniques and the optimized microbeads were subjected to in vivo pharmacokinetic and in vitro cytotoxicity studies using HT 29 cell lines. The results revealed that 5-FU-loaded microbeads exhibited significantly more cytotoxic, and bioavailability was found to be nearly doubled as compared to pure drugs. Conclusion: 5-FU-loaded microbeads can be developed and optimized successfully by using quality by design approach and coating with eudragit S100, which can be targeted to the colon for the effective treatment of colorectal cancer.