高良姜素介孔二氧化硅纳米粒胃漂浮片制备、药动学及毒性评价

胡晓凤; 胡赛赛; 崔锋

doi:10.13748/j.cnki.issn1007-7693.20251933

高良姜素介孔二氧化硅纳米粒胃漂浮片制备、药动学及毒性评价

Preparation, Pharmacokinetics and Toxicity Evaluation of Galangin Mesoporous Silica Nanoparticles Gastric Floating Tablets

摘要

摘要:
目的制备高良姜素介孔二氧化硅纳米粒胃漂浮片(galangin mesoporous silica nanoparticles gastric floating tablets，Gal-MSNs-GFT)，评价口服药动学行为及相对生物利用度。
方法制备高良姜素介孔二氧化硅纳米粒(galangin mesoporous silica nanoparticles，Gal-MSNs)，采用Box-Behnken设计-响应面法优化Gal-MSNs-GFT处方。扫描电镜观察介质中MSNs-GFT形貌，考察Gal-MSNs-GFT在pH 0.8~5.0介质中的释药行为。以高良姜素普通片为参考，比较Gal-MSNs-GFT在比格犬体内的口服药动学行为及相对生物利用度。比较首次和末次给药后血浆中高良姜素含量，计算达峰时间(t_max)、血药浓度(C_max)和半衰期(t_1/2)等毒动学参数。观察动物一般状态，进行血液学、生化指标检查等。
结果 Gal-MSNs-GFT最佳处方为HPMC K15M、十六醇和NaHCO₃用量分别为29.64%、12.13%和15.32%。Gal-MSNs-GFT在pH 0.8~5.0中可维持缓慢释药行为，12 h累积释放度>85%，释药行为均符合一级动力学模型。比格犬体内药动学结果显示，Gal-MSNs-GFTt_max延后至(4.39±0.84)h，C_max增加至(583.07±176.65)ng·mL⁻¹，t_1/2延长至(5.84±1.98)h，Gal-MSNs-GFT相对生物利用度提高至5.42倍。Beagle犬重复给药4周，各剂量下Gal-MSNs-GFT在Beagle 犬体内未见明显蓄积。Gal-MSNs-GFT高剂量组可能对血液系统、肝脏和肾脏有轻微影响，恢复期症状消失。
结论 Gal-MSNs-GFT工艺重复性良好，释药行为平稳，显著提高了高良姜素生物利用度。

Abstract:
OBJECTIVE To prepare galangin mesoporous silica nanoparticles gastric floating tablets(Gal-MSNs-GFT), and to evaluate its oral pharmacokinetic behavior and relative bioavailability.
METHODS Galangin mesoporous silica nanoparticles(Gal-MSNs) was prepared firstly, and then Box-Behnken design-response surface method was employed to optimize formulation of Gal-MSNs-GFT. Scanning electron microscope was used to observe the morphology of MSNs-GFT in the medium, and the release behavior of Gal-MSNs-GFT in pH 0.8−5.0 medium were also studied. Taking galangin conventional tablets as reference, oral pharmacokinetic behavior and relative bioavailability of Gal-MSNs-GFT in beagle dogs were investigated. Compared the plasma content of galangin after the first and last administration, and calculated the toxicokinetic parameters such as time to peak concentration(t_max), peak plasma concentration(C_max) and elimination half-life(t_1/2). Observed the general condition of the animals, and checked hematology and biochemical indexes.
RESULTS Optimal formulation of Gal-MSNs-GFT: Dose of HPMC K15M, hexadecyl alcohol and NaHCO₃ were 29.64%, 12.13% and 15.32%, respectively. Gal-MSNs-GFT could maintain sustained-release behavior in the medium of pH 0.8 to 5.0, cumulative release rate in 12 h was more than 85%, and the drug release behavior conformed to the first-order kinetic model. Pharmacokinetic results in beagle dogs showed that the t_max of Gal-MSNs-GFT was delayed to (4.39±0.84)h, C_max was enhanced to (583.07±176.65)ng·mL⁻¹, t_1/2 was prolonged to (5.84±1.98)h, and the relative bioavailability of Gal-MSNs-GFT was increased to 5.42 times. After 4-week repeated dosing in Beagle dogs, no obvious accumulation of Gal-MSNs-GFT was observed at at each dose. The high-dose group of Gal-MSNs-GFT might have slight effects on the hematopoietic system, liver and kidney, and the symptoms disappeared during the recovery period.
CONCLUSION The repeatability of Gal-MSNs-GFT preparation process is good, release behavior is stable, and the bioavailability of galangin in vivo is significantly improved.

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