1 Biologics, Department of Pharmacy, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Biologics, Department of Pharmacy, Faculty of Health and Medical Sciences, Københavns Universitet
implication of lipase digestibility on oral bioavailability, in vivo antioxidant activity, and in vitro-in vivo relationships
The present investigation reports implications of the lipase digestibility of lyotropic liquid crystalline nanoparticles (LCNPs) on the oral bioavailability, in vivo antioxidant potential, and in vitro-in vivo relationship (IVIVR) of CoQ10 loaded LCNPs prepared from glyceryl monooleate (GLCQ) and phytantriol (PLCQ). Exhaustive optimization of the process variables was carried out, and optimized lyophilized formulations were found to have particle sizes of 140.45 ± 5.47 nm and 238.42 ± 8.35 nm and a polydispersity index (PDI) of 0.15 ± 0.01 and 0.22 ± 0.03 for GLCQ and PLCQ, respectively. The entrapment efficiency at 10% theoretical loading was found to be >90% in both the cases. The morphological characteristics of the developed formulations were assessed using high resolution transmission electron microscopy and small-angle X-ray scattering analysis, which showed hexagonal (HII) structure. The developed formulations were also found to be stable in simulated gastrointestinal fluids for the stipulated period of time. The in vitro drug release studies revealed a bimodal sustained release drug profile with Higuchi type release kinetics as the best fit release model for both the formulations. The best fit release models were found to be of the Hixson Crowell type in the case of GLCQ when carried out in lipase rich media, suggestive of matrix erosion and subsequent formation of secondary structures, which was further corroborated by carrier degradation studies. Furthermore, 9.1- and 10.67-fold increase in Caco-2 cell uptake was observed in the case of GLCQ and PLCQ, respectively, attributed to the formation of the virtual channel pathway as a probable absorption mechanism. Consequently, 7.09- and 8.67-fold increase in oral bioavailability was observed in the case of GLCQ and PLCQ, respectively. The IVIVR was also established with r(2) values in the order of 0.996 and 0.999 for GLCQ and PLCQ, respectively, in contrast to that of 0.484 for free CoQ10. Finally, in vivo prophylactic antioxidant efficacy against the STZ-treated rats using various markers such as GSH, LDH, SOD, MDA, glucose level, and body weight showed significantly higher antioxidant activity of CoQ10-LCNPs as compared to that of free CoQ10. In a nutshell, the developed formulation strategy poses great potential in improving the oral bioavailability of difficult-to-deliver drugs such as CoQ10.
Molecular Pharmaceutics, 2014, Vol 11, Issue 5, p. 1435-49