目的 制备绞股蓝皂苷-丹参酮Ⅱ_A/磷脂酰胆碱复合物纳米混悬剂（Gyp-Tan Ⅱ_A/PC-NPs），考察体内药动学和抗肺纤维化作用。方法 溶剂挥发法制备丹参酮Ⅱ_A/磷脂酰胆碱复合物（Tan Ⅱ_A/PC），单因素实验联合Box-Behnken设计-响应面法（BBD-RSM）优化Gyp-Tan Ⅱ_A/PC-NPs处方工艺。测定粒径、多分散指数（PDI）、Zeta电位和载药量，扫描电镜观察GypTan Ⅱ_A/PC-NPs微观形貌，X射线粉末衍射法（XRPD）和差示扫描量热（DSC）分析药物晶型。考察Gyp-Tan Ⅱ_A/PC-NPs在不同介质中的溶解度和体外释药行为。以泊洛沙姆188和泊洛沙姆407为基质制备丹参酮Ⅱ_A纳米混悬剂（Tan Ⅱ_A-NPs）比较Tan Ⅱ_A、物理混合物（Tan Ⅱ_A+Gyp+PC，比例同Gyp-Tan Ⅱ_A/PC-NPs）、Tan Ⅱ_A-NPs和Gyp-Tan Ⅱ_A/PC-NPs口服药动学行为，计算主要药动学参数及其口服吸收相对生物利用度。经气管软骨环间隙注入博来霉素(5 mg·kg^-1)建立小鼠肺纤维化模型，比较Tan Ⅱ_A、Tan Ⅱ_A-NPs和Gyp-Tan Ⅱ_A/PC-NPs对肺指数，肺组织羟脯氨酸水平、肿瘤坏死因子（TNF）-α、转化生长因子（TGF）-β1及血清中白细胞介素（IL）-6的影响。苏木精-伊红（HE）染色观察肺组织病理学变化，Masson染色观察肺组织纤维化程度。结果 Gyp-Tan Ⅱ_A/PC-NPs最佳处方工艺：绞股蓝皂苷质量分数为0.21%，均质压力为80.00 MPa，均质次数为7次。Gyp-Tan Ⅱ_A/PC-NPs平均粒径为（229.72±4.26）nm,PDI值为0.206±0.012,Zeta电位为（-27.07±0.84）m V。Gyp-Tan Ⅱ_A/PC-NPs微观形貌为不规则纳米颗粒，Tan Ⅱ_A在Tan Ⅱ_A/PC、Gyp-Tan Ⅱ_A/PC-NPs中由晶态转变为无定形态。Gyp-Tan Ⅱ_A/PC-NPs极大提高了Tan Ⅱ_A溶解度及溶出度。口服药动学结果显示，Gyp-Tan Ⅱ_A/PC-NPs达峰时间(t_max)提前至（0.97±0.21）h，达峰浓度(C_max)增加至（1 290.61±302.39）ng·mL^-1，相对口服吸收生物利用度提高至4.26倍。与Tan Ⅱ_A组比较，Gyp-Tan Ⅱ_A/PC-NPs高剂量的肺指数、羟脯氨酸、TNF-α、TGF-β1和IL-6水平均极显著性下降（P<0.01）。HE染色证实Gyp?Tan Ⅱ_A/PC?NPs能有效改善肺组织病变，Masson染色显示其可抑制胶原沉积，显著减轻炎细胞浸润与肺纤维化程度。结论 Gyp-Tan Ⅱ_A/PC-NPs极大促进了Tan Ⅱ_A体内吸收，增强其抗肺纤维化作用。

Objective To prepare gypenosides tanshinone Ⅱ_A/phosphatidylcholine complex nanosuspensions（Gyp-Tan Ⅱ_A/PC-NPs） and investigate its in vivo pharmacokinetics and anti-pulmonary fibrosis effects. Methods The solvent evaporation method was used to prepare tanshinone Ⅱ_A/phosphatidylcholine complex（Tan Ⅱ_A/PC）. The single factor experiment combined with Box-Behnken design-response surface methodology（BBD-RSM） was used to optimize the prescription and process of Gyp-Tan Ⅱ_A/PC-NPs. The particle size, polydispersity index（PDI）, Zeta potential and drug loading were determined. The microscopic morphology of Gyp-Tan Ⅱ_A/PC-NPs was observed by scanning electron microscopy. The crystal form of the drug was analyzed by X-ray powder diffraction（XRPD） and differential scanning calorimetry（DSC）. The solubility and in vitro release behavior of Gyp-Tan Ⅱ_A/PC-NPs in different media were investigated. Tan Ⅱ_A-NPs were prepared using poloxamer 188 and poloxamer 407 as the matrix. The oral pharmacokinetic behaviors of Tan Ⅱ_A, physical mixture（Tan Ⅱ_A + Gyp + PC, in the same proportion as Gyp-Tan Ⅱ_A/PC-NPs）, Tan Ⅱ_A-NPs and GypTan Ⅱ_A/PC-NPs were compared. The main pharmacokinetic parameters and oral absorption relative bioavailability were calculated. A mouse model of pulmonary fibrosis was established by injecting bleomycin(5 mg·kg^-1) into the tracheal cartilage ring gap. The effects of Tan Ⅱ_A, Tan Ⅱ_A-NPs and Gyp-Tan Ⅱ_A/PC-NPs on lung index, hydroxyproline level in lung tissue, TNF-α, TGF-β1 and IL-6 in serum were compared. The pathological changes of lung tissue were observed by hematoxylin-eosin（HE） staining, and the degree of pulmonary fibrosis was observed by Masson staining. Results The optimal prescription and process of Gyp-Tan Ⅱ_A/PC-NPs were as follows: the mass fraction of Gyp was 0.21%, the homogenization pressure was 80 MPa, and the homogenization times were seven. The average particle size of Gyp-Tan Ⅱ_A/PC-NPs was（229.72 ± 4.26） nm, the PDI value was（0.206 ± 0.012）, and the Zeta potential was（-27.07 ± 0.84） mV. The microscopic morphology of Gyp-Tan Ⅱ_A/PC-NPs was irregular nanoparticles. Tan Ⅱ_A changed from crystalline to amorphous in Tan Ⅱ_A/PC and Gyp-Tan Ⅱ_A/PC-NPs. Gyp-Tan Ⅱ_A/PC-NPs greatly increased the solubility and dissolution rate of Tan Ⅱ_A. The oral pharmacokinetic results showed that the peak time(t_max) of Gyp-Tan Ⅱ_A/PC-NPs was advanced to（0.97 ± 0.21） h, the peak concentration(C_max) increased to（1 290.61 ± 302.39） ng·mL^-1, and the relative oral absorption bioavailability increased to 4.26 times. Compared with the Tan Ⅱ_A group, the lung index, hydroxyproline, TNF-α, TGF-β1 and IL-6 levels in the highdose Gyp-Tan Ⅱ_A/PC-NPs group were significantly decreased（P < 0.01）. HE staining confirmed that Gyp-Tan Ⅱ_A/PC-NPs could effectively improve the pathological changes of lung tissue, and Masson staining showed that it could inhibit collagen deposition and significantly reduce the degree of inflammatory cell infiltration and pulmonary fibrosis. Conclusion Gyp-Tan Ⅱ_A/PC-NPs significantly promoted the in vivo absorption of Tan Ⅱ_A and enhanced its anti-pulmonary fibrosis effect.

R285.5;R283.6

河南省科技攻关项目(252102310406); 郑州市基础研究及应用基础研究项目(ZZSZX202420); 2025年度郑州市医疗卫生领域科技创新项目(2025YLZDJH423); 国家级大学生创新项目(202511834011); 黄河科技学院大学生创新项目(2025xscxcy087)