Evaluation of pH Responsive Flipping Mechanism of 5-Fluorouracil Loaded LLC System for Colon Targeting

Purpose Lyotropic liquid crystals (LLC) capable of flipping their structure according to varying pH environment of the GI tract were developed for colon-targeted delivery of 5-fluorouracil (5-FU). Methods A pH-sensitive LLC system loaded with 5-FU has been prepared by using different ratios of monoolein (MO) and oleic acid (OA) to facilitate drug targeting to the colon. The LLC batches were prepared utilizing different buffers, i.e., HCl buffer with pH 1.2 (indicative of gastric pH), acetate buffer with pH 4.5 (indicative of duodenum fluid pH), HEPES buffer with pH 6.8 (indicative of small intestinal fluid pH), and HEPES buffer with pH 7.4 (colon and rectum pH). The formulations were confirmed for liquid crystal phase formed by polarized light microscopy (PLM) and characterized by DSC, FESEM, drug content, rheology, texture analysis, in vitro drug release study and in vivo gamma-scintigraphic study. Results The PLM study confirmed the occurrence of both hexagonal and cubic phase liquid crystal depending on the pH and ratio of MO:OA used, which is further supported by the rheological determinations. The release study confirmed insignificant release of drug in the pH 1.2, pH 4.5, and pH 6.8 up to 5 h and major drug release in the colon and rectum pH up to 26 h showing more than 90% drug release in the colonic region by the formulation containing 40% MO and 60% OA. Conclusions The 5-FU release pattern from the pH-sensitive LLC formulation exhibits slow and extended release over longer periods of time owing to its ability to remain in less mucoadhesive hexagonal phase at lower pH environment causing slower release of drug and transforming into more mucoadhesive cubic phase at higher pH causing faster release of drug.

Automated summary

The pH-sensitive Lyotropic liquid crystals (LLC) can flip their structure according to different pH environments, facilitating colon-targeted release of 5-FU. The formulation containing 40% MO and 60% OA showed the best drug release performance in the colon and rectum pH conditions, with slow and extended release over longer periods of time.