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Enhancement of oral bioavailability of salmon calcitonin through chitosan modified dual-drug loaded nanoparticles

Lin Liu  Hui Yang  Yan Lou  Jiaying Wu  Jing Miao  Xiaoyang Lu  Jianqing Gao  
【摘要】:Since numerous challenges limiting effective oral delivery of protein and peptide drugs, a promising strategy for oral administration, salmon calcitonin(sCT) combined with puerarin(PR) as digestive enzymes inhibitor, was performed and the oral delivery property was evaluated. A chitosan(CS) modified dual-drug loaded nanoparticles(NPs) simultaneously containing sCT and PR(CS-sCT/PR-NPs) was prepared by optimized double emulsification solvent evaporation method to achieve particles sized at(190.32±2.65) nm and Zeta potential of(16.5±1.08) mV. This oral delivery system showed efficient encapsulation of sCT(75.7%) and PR(50.9%), protection for encapsulated sCT and PR from releasing too fast in SGJ(pH 1.2), and sustained-release behavior in PBS(pH=7.4). Moreover, CS-sCT/PRNPs had a capability of sequential drug release that PR was partially released prior to sCT, providing a possibility for PR to play a role of enzyme inhibitor before sCT release. The in vitro stability studies indicated that CS-sCT/PRNPs were more stable than CS-sCT-NPs in simulated intestinal ·uid in the absence of pancreatinum. An in vitro cell evaluation demonstrated that the internalization of FITC-sCT by Caco-2 cells was increased when incorporated into NPs, either sole drug loaded or dual drug loaded, compare with free sCT. In vivo, the developed sCT loaded NPs showed increased elimination half-life compared with i.v. sCT solution in rats. Notably, a significant increase of AUC of sCT in the CS-sCT/PR-NPs group was observed compared to that in the CS-sCT-NPs group, and the oral absolute bioavailability of sCT in CS-sCT/PR-NPs of 12.52 ± 1.83% was approximately 1.74-fold higher than that in NPs without co-loaded with PR. In conclusion, the CS based NPs and the introduction of PR as a protease inhibitor improve the oral bioavailability of sCT and have the potential for the oral delivery of peptide drug.

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