Supersaturated Drug Delivery System of Oxyberberine Based on Cyclodextrin Nanoaggregates: Preparation, Characterization, and in vivo Application

Abstract

Ziwei Huang,1 Shanli Zhang,1 Zehui Qin,1 Gaoxiang Ai,1 Minhua Li,1 Shiting Gong,1 Yuhong Liu,1 Huifang Zeng,2 Jiannan Chen,1 Ziren Su,1 Zhengquan Lai3 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 3Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Zhengquan Lai, Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, Guangdong, People’s Republic of China, Email [email protected] Ziren Su, School of pharmaceutical sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China, Email [email protected]: Oxyberberine (OBB), one of the main metabolites of berberine derived from intestinal and erythrocyte metabolism, exhibits appreciable anti-hyperuricemic activity. However, the low water solubility and poor plasma concentration–effect relationship of OBB hamper its development and utilization. Therefore, an OBB-hydroxypropyl-β-cyclodextrin (HP-β-CD) supersaturated drug delivery system (SDDS) was prepared and characterized in this work.Methods: OBB-HP-β-CD SDDS was prepared using the ultrasonic-solvent evaporation method and characterized. Additionally, the in vitro and in vivo release experiments were conducted to assess the release kinetics of OBB-HP-β-CD SDDS. Subsequently, the therapeutic efficacy of OBB-HP-β-CD SDDS on hyperuricemia (HUA) was investigated by means of histopathological examination and evaluation of relevant biomarkers.Results: The results of FT-IR, DSC, PXRD, NMR and molecular modeling showed that the crystallized form of OBB was transformed into an amorphous OBB-HP-β-CD complex. Dynamic light scattering indicated that this system was relatively stable and maintained by formation of nanoaggregates with an average diameter of 23 nm. The dissolution rate of OBB-HP-β-CD SDDS was about 5 times higher than that of OBB raw material. Furthermore, the AUC0-t of OBB-HP-β-CD SDDS (10.882 μg/mL*h) was significantly higher than that of the raw OBB counterpart (0.701 μg/mL*h). The oral relative bioavailability of OBB-HP-β-CD SDDS was also enhanced by 16 times compared to that of the raw material. Finally, in vivo pharmacodynamic assay showed the anti-hyperuricemic potency of OBB-HP-β-CD SDDS was approximately 5– 10 times higher than that of OBB raw material.Conclusion: Based on our findings above, OBB-HP-β-CD SDDS proved to be an excellent drug delivery system for increasing the solubility, dissolution, bioavailability, and anti-hyperuricemic potency of OBB. Keywords: oxyberberine, cyclodextrin, supersaturated drug delivery systems, pharmacokinetics, hyperuricemia

Keywords

• oxyberberine
• cyclodextrin
• supersaturated drug delivery systems
• pharmacokinetics
• hyperuricemia