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. 2024 Jun 6:19:5297-5316.
doi: 10.2147/IJN.S464994. eCollection 2024.

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

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 Lai  3
Affiliations

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

Ziwei Huang et al. Int J Nanomedicine. .

Abstract

Propose: 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: cyclodextrin; hyperuricemia; oxyberberine; pharmacokinetics; supersaturated drug delivery systems.

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Conflict of interest statement

Dr Ziwei Huang and Dr Ziren Su report a patent A type of protoberberine-based oxidized cyclodextrin complex and its preparation method and application issued to CN202310409421.9. The authors declare no other conflicts of interest in this work.

Figures

None
Graphical abstract
Figure 1
Figure 1
Preparation and optimization of OBB-HP-β-CD SDDS. The structures of OBB (A) and HP-β-CD (B). Effect of different excipients on the solubility of OBB (C). Phase solubility diagram for OBB-HP-β-CD system (D). Effect of feed ratio (E), temperature (F) and reaction time (G) on the inclusion efficiency. The appearances of different samples before (H) and after (I) dissolved in water.
Figure 2
Figure 2
FT-IR (A), PXRD (B), and DSC (C) thermograms of OBB, HP-β-CD, OBB-HP-β-CD physical mixture, and OBB-HP-β-CD SDDS. The figures were generated by GraphPad prism 8.
Figure 3
Figure 3
1H NMR diffractogram (A) of OBB, HP-β-1CD, OBB-HP-β-CD physical mixture, OBB-HP-β-CD SDDS and 1H-1H NOESY diffractogram (B) of OBB-HP-β-CD SDDS.
Figure 4
Figure 4
Surface view of the binding configuration of OBB and HP-β-CD in molecular modeling, showing the 9 or 10-methoxyl of OBB inside the cavity of HP-β-CD. (A) Front view. (B) Top view. The figures were generated by PyMOL Molecular Graphics System (version 2.5).
Figure 5
Figure 5
The formation of nanoaggregates in OBB-HP-β-CD SDDS to maintain supersaturation. The shift of particle size and its potential nanoaggregates structural diagram (A), and its supersaturated stability in artificial gastric (B) and intestinal (C) juice (n = 3). *p < 0.05 and **p < 0.01 vs 4 mg/mL group.
Figure 6
Figure 6
Dissolution profiles of OBB raw material and OBB-HP-β-CD SDDS in artificial gastric (A) and intestinal (B) juice (n = 3). ##p < 0.01 vs OBB raw material; **p < 0.01 vs physical mixture of OBB and HP-β-CD.
Figure 7
Figure 7
Plasma concentration–time curves of OBB raw material and OBB-HP-β-CD SDDS in rats (n = 6). **p < 0.01 vs p.o. OBB raw material.
Figure 8
Figure 8
Effect of OBB-HP-β-CD SDDS on serum levels of UA (A), CRE (B) and BUN (C), and kidney index (D) in HUA mice. Data are shown as mean ± SD (n = 10). ##p < 0.01 vs Con group. *p < 0.05 and **p < 0.01 vs HUA group.
Figure 9
Figure 9
H&E staining (200 ×) and histopathological score of kidney sections in HUA mice (n = 3). Black arrow: atrophic glomeruli and unusual tubular structure; black arrowhead: normal renal tubular and glomeruli. ##p < 0.01 vs Con group; **p < 0.01 vs HUA group.
Figure 10
Figure 10
Effect of OBB-HP-β-CD SDDS on inflammatory cytokines in HUA mice (n = 10). (A) TNF-α, (B) IL-1β, and (C) IL-6. ##p < 0.01 vs Con group; **p < 0.01 vs HUA group.
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