目的 制备黄豆苷元介孔二氧化硅纳米粒缓释片（daidzein mesoporous silica nanoparticles sustained-release tablets，Dai-MSNs-SRT），并考察Beagle犬的口服药动学行为。方法 选择羟丙基甲基纤维素K4M（hydroxypropyl methyl cellulose K4M，HPMC K4M）用量、羧甲基淀粉钠（carboxyl methyl starch sodium，CMS-Na）用量和聚乙二醇400（polyethylene glycol 400，PEG 400）用量为主要影响因素，Dai-MSNs-SRT在2、6、12 h累积释放率的综合评分为响应值，采用Box-Behnken设计-效应面法优化IMP-SD-HMSRT最佳处方优化处方工艺。对Dai-MSNs-SRT释药模型和释药机制进行探讨。按10 mg/kg（以黄豆苷元计）进行ig，比较Dai-MSNs-SRT口服药动学行为，并计算相对口服生物利用度。采用Loo-Rigelman法评价Dai-MSNs-SRT体内外相关性。结果 Dai-MSNs-SRT最佳处方为Dai-MSNs粉末350 mg/片，HPMC K4M用量为15.2%，CMS-Na用量为9.5%，PEG 400用量为2.1%。Dai-MSNs-SRT缓释特征明显，12 h累积释放率达94.87%。Dai-MSNs-SRT体外释药符合Higuchi模型，释药机制为扩散和骨架溶蚀并存。药动学结果显示，Dai-MSNs-SRT血药浓度（C_max）波动幅度小，达峰时间（t_max）由（1.53±0.42）h延后至（4.26±0.44）h，半衰期（t_1/2）由（3.26±0.56）h延长至（6.63±2.17）h，与上市品相比，相对生物利用度提高至其1.88倍。Dai-MSNs-SRT在pH7.4磷酸盐缓冲液中体外释放与体内吸收相关性良好。结论 Dai-MSNs-SRT工艺重复性良好，C_max波动幅度小，提高了其生物利用度。

Objective To prepare daidzein mesoporous silica nanoparticles sustained-release tablets (Dai-MSNs-SRT), and investigate its oral pharmacokinetic behavior in Beagle dogs. Methods Hydroxypropyl methyl cellulose K4M (HPMC K4M) dose, carboxyl methyl starch sodium (CMS-Na) dose and polyethylene glycol 400 (PEG 400) dose were selected as main influencing factors, composite score of cumulative rate of 2, 6, and 12 h was used as response value, Box-Behnken design-response surface methodology (BBD-RSM) was employed to optimize formulation of Dai-MSNs-SRT. Release model and release mechanism were also studied. Dai-MSNs-SRT was orally administered to Beagle dogs (10 mg/kg), pharmacokinetic behavior of Dai-MSNs-SRT was compared and relative oral bioavailability was calculated. Loo-Rigelman method was used for the evaluation of in vivo and in vitro correlation. Results Optimal formulation of Dai-MSNs-SRT: Dai-MSNs powder was 350 mg/tablet, HPMC K4M dose was 15.2%, CMS-Na dose was 9.5% and PEG 400 dose was 2.1%. Sustained-release characteristic of Dai-MSNs-SRT was obvious and cumulative release rate in 12 h was up to 94.87%. Drug release in vitro of Dai-MSNs-SRT was better accorded with Higuchi model, and release mechanism was diffusion and matrix degradation. Pharmacokinetic results showed that C_max of Dai-MSNs-SRT fluctuated slightly, t_max was delayed from (1.53 ±0.42) h to (4.26 ±0.44) h and t_1/2 was prolonged from (3.26 ±0.56) h to (6.63 ±2.17) h. Relative bioavailability of Dai-MSNs-SRT was enhanced to 1.88 times comparing to commercial tablets. In vitro release behavior of Dai-MSNs-SRT in pH 7.4 phosphate buffer saline was better associated with its absorption in vivo. Conclusion Reproducibility of Dai-MSNs-SRT was favorable, C_max fluctuated slightly and relative bioavailability was also enhanced.

R283.6

河南省高等学校重点科研项目计划（23B310010）