目的 制备叶黄素介孔二氧化硅纳米粒胃漂浮片（Lut-MSNs-GFT），评价其口服药动学行为及对胃溃疡治疗作用。方法 浸渍法制备叶黄素介孔二氧化硅纳米粒（Lut-MSNs）粉末，测定其溶解度、晶型特征及在模拟胃液中的稳定性；单因素实验考察羟丙基甲基纤维素（HPMC） K15M、十六醇和NaHCO₃用量对Lut-MSNs-GFT释药行为的影响；以2、6、12 h累积释放度综合评分为响应值，通过Box-Behnken设计-效应面法优化Lut-MSNs-GFT处方；扫描电镜观察其微观形态，并考察Lut-MSNs-GFT储存稳定性。将6只Beagle犬随机分为叶黄素胶囊组和Lut-MSNs-GFT组，采用双周期交叉实验进行体内药动学研究。建立家兔胃溃疡模型，计算溃疡抑制率；采用试剂盒法测定血清中一氧化氮（NO）、超氧化物歧化酶（SOD）、丙二醛（MDA）和前列腺素E₂（PGE₂）含量。取部分胃组织进行苏木精-伊红（HE）染色进行病理组织学评价。结果 LutMSNs-GFT最优处方为HPMC K15M用量34.51%，十六醇用量11.06%，NaHCO₃用量9.68%。Lut-MSNs-GFT在2、6、12 h累积释放度分别为25.68%、62.05%、94.16%，漂浮滞后时间（74.19± 5.58） s，漂浮时间（11.47± 0.65） h。药动学结果显示，与普通胶囊相比，Lut-MSNs-GFT达峰时间（t_max）延后至（6.59± 1.42） h，半衰期（t_1/2）延长至（9.42± 2.85） h，达峰浓度（C_max）提高至（514.20± 133.73） ng·mL^-1，相对生物利用度提高至3.18倍。家兔药效学实验表明，Lut-MSNs-GFT高剂量组溃疡抑制率达64.83%；血清中NO、SOD水平极显著升高（P＜0.01），MDA水平显著降低（P＜0.05）。HE染色结果显示，高剂量组胃黏膜病理损伤明显减轻。结论 Lut-MSNs-GFT制备工艺稳定、重复性良好，可显著提高叶黄素口服生物利用度，并增强其对胃溃疡的治疗作用。

Objective To prepare lutein-mesoporous silica nanoparticles-gastric floating tablets (Lut-MSNs-GFT) and evaluate its oral pharmacokinetic behavior and therapeutic effect on gastric ulcers. Methods Lutein-mesoporous silica nanoparticles (Lut-MSNs) powder was prepared by the impregnation method, and its solubility, crystal form characteristics, and stability in simulated gastric fluid were determined. The effects of the amounts of hydroxypropyl methylcellulose (HPMC) K15M, cetyl alcohol, and NaHCO₃ on the drug release behavior of Lut-MSNs-GFT were investigated by single-factor experiments. The cumulative release at 2, 6, and 12 h was used as the response value, and the Box-Behnken design-response surface methodology was employed to optimize the Lut-MSNs-GFT formulation. The microstructure was observed by scanning electron microscopy, and the storage stability of Lut-MSNs-GFT was evaluated. Six Beagle dogs were randomly divided into lutein capsule group and Lut-MSNs-GFT group, and a double-period crossover experiment was conducted for in vivo pharmacokinetic studies. A rabbit model of gastric ulcer was established, and the ulcer inhibition rate was calculated. The contents of nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), and prostaglandin E2 (PGE2) in serum were determined by kit method. Part of the gastric tissue was stained with hematoxylin-eosin (HE) for histopathological evaluation. Results The optimal formulation of Lut-MSNs-GFT was HPMC K15M 34.51%, cetyl alcohol 11.06%, and NaHCO3 9.68%. The cumulative release of Lut-MSNs-GFT at 2, 6, and 12 h was 25.68%, 62.05%, and 94.16%, respectively. The floating lag time was (74.19±5.58) s, and the floating time was (11.47±0.65) h. The pharmacokinetic results showed that compared with the ordinary capsule, the peak time (t_max) of Lut-MSNs-GFT was delayed to (6.59±1.42) h, the half-life (t1/2) was prolonged to (9.42±2.85) h, and the peak concentration (C_max) was increased to (514.20±133.73) ng·mL^-1, with a relative bioavailability of 3.18 times. The pharmacodynamic experiments in rabbits showed that the ulcer inhibition rate of the high-dose group of Lut-MSNs-GFT was 64.83%; the levels of NO and SOD in serum were significantly increased (P<0.01), and the level of MDA was significantly decreased (P<0.05). The HE staining results showed that the pathological damage of gastric mucosa in the high-dose group was significantly alleviated. Conclusion The preparation process of Lut-MSNs-GFT is stable and reproducible, which can significantly improve the oral bioavailability of lutein and enhance its therapeutic effect on gastric ulcers.

R283;R285.5

河南省科技攻关项目（232102310384）