Development of Novel lipid Nanoparticles for oral Bioavailability Enhancement of Irinotecan: In-vitro and In-vivo Investigations

Background: Irinotecan is indicated as a first line treatment for metastatic colorectal cancer. However, chemotherapy with irinotecan is restricted to i.v. route owing to poor and erratic oral bioavailability due to its excessive intestinal efflux by P-glycoprotein. Objective: Aim of the present study is to improve the oral pharmacokinetic profile of irinotecan (IRT) by merging the attributes of nano-particulate system and P-glycoprotein (P-gp) modulation activity of excipients. Methods: Gelucire 44/14 solid lipid nanoparticles (SLN) were developed and optimized by Box Behnken design. Optimized formulation was evaluated for various in vitro attributes and in vivo pharmacokinetic profile. Results: Size of optimized SLN was found to be 179.8±15.3 nm with polydispersity index, 0.367±0.029 and drug entrapment, 78.2±4.6%. SLN showed biphasic release profile i.e. initial burst release followed by sustained release. Differential scanning calorimetric (DSC) and X-ray diffractometric (XRD) analyses of SLN demonstrated the loss of drug’s crystallinity in SLN. Further, confocal laser scanning microscopy showed higher permeation of Rhodamine 123 (P-gp substrate) across intestinal epithelium through SLN when compared with free rhodamine 123 solution. Furthermore, in-vivo studies exhibited superior pharmacokinetic profile; significantly high (p<0.001) Cmax (1471.6±190.9 ng/mL) was attained through SLN when compared with Cmax of oral suspension (1113.5±125.5 ng/mL), similarly, high Tmax (p<0.001) was observed which revealed sustained effect of SLN. Conclusively, 2.79 folds improvement in oral bioavailability of IRT could be achieved through SLN when compared with oral suspension. Conclusion: Outcomes of studies suggested the potential of developed SLN for oral delivery of irinotecan and possibility to replace pre-existing intravenous therapy.