Published online Feb 21, 2017. doi: 10.3748/wjg.v23.i7.1147
Peer-review started: October 14, 2016
First decision: December 1, 2016
Revised: December 16, 2016
Accepted: January 4, 2017
Article in press: January 4, 2017
Published online: February 21, 2017
Processing time: 129 Days and 17.1 Hours
To develop a colon-targeting bioreversible delivery system for β-boswellic acid (BBA) and explore utility of its prodrugs in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats.
Synthesis of 4 co-drugs of BBA with essential amino acids was achieved by CDI coupling, followed by their spectral characterization. In vitro kinetics were studied by HPLC in aqueous buffers, homogenates of gastrointestinal tract and fecal matter. In vivo kinetic studies were performed in Wistar rat plasma, urine and feces. The prodrugs were screened in TNBS-induced colitis modeled Wistar rats. Statistical significance was assumed at P < 0.05, P < 0.01, P < 0.001 when compared with disease controls using one-way and two-way ANOVAs.
Prodrugs were stable in 0.05 mol/L HCl buffer (pH 1.2) and stomach homogenates. Negligible hydrolysis was observed in phosphate buffer and intestinal homogenates. Substantial release (55%-72% and 68%-86%) of BBA was achieved in rat fecal matter and homogenates of colon. In vivo studies of BBA with L-tryptophan (BT) authenticated colon-specific release of BBA. But, surprisingly substantial concentration of BBA was seen to reach the systemic circulation due to probable absorption through colonic mucosa. Site-specifically enhanced bioavailability of BBA could be achieved in colon, which resulted in demonstration of significant mitigating effect on TNBS-induced colitis in rats without inducing any adverse effects on stomach, liver and pancreas. Prodrug of BT was found to be 1.7% (P < 0.001) superior than sulfasalazine in reducing the inflammation to colon among all prodrugs tested.
The outcome of this study strongly suggests that these prodrugs might have dual applicability to inflammatory bowel disease and chronotherapy of rheumatoid arthritis.
Core tip: Boswellic acids (BAs) are traditionally used in the treatment of inflammatory diseases and are effective in the treatment of inflammatory bowel disease (IBD) in particular, but they undergo extensive metabolism that results in low oral bioavailability. Colon-targeted delivery of BA was achieved by designing prodrugs that deliver BA site-specifically. The synthesized prodrugs were designed by semi-synthetic approach, wherein β-boswellic acid (BBA) was derivatized into a bioreversible delivery system by incorporation of amino acids as promoities for targeted delivery to inflamed colon in IBD. Prodrug of BBA with L-tryptophan (BT) was 1.7-times more effective than sulfasalazine (SLZ) in 2,4,6-trinitrobenzene sulfonic acid-induced colitis in Wistar rats. In vivo behavior of prodrug BT was very interesting and similar to SLZ, which is known to treat local inflammation in IBD as well as in rheumatoid arthritis (RA). The outcome of this study strongly suggests that these prodrugs might have dual applicability to IBD and chronotherapy of RA.