College of Pharmacy, Dankook University, Cheon-an, 31116, South Korea.
BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, 41566, South Korea.
Arch Pharm Res. 2022 Oct;45(10):743-760. doi: 10.1007/s12272-022-01407-0. Epub 2022 Sep 30.
This study aimed to develop a solid dispersion formulation of silymarin (Silymarin-SD) using freeze-drying method to enhance its oral bioavailability (BA) by inhibiting the intestinal first-pass effect and increasing its solubility and permeability. Silymarin-SD formulation (i.e., silymarin:tween 80:hydroxypropyl cellulose (HPC) = 1:1:3 (w/w/w) significantly increased silymarin permeability in the duodenum, jejunum, and ileum by decreasing the efflux ratio of silymarin and by inhibiting silymarin-glucuronidation activity, in which tween 80 played a crucial role. As a result, orally administered Silymarin-SD formulation increased plasma silymarin concentrations and decreased silymarin-glucuronide in rats compared with silymarin alone and silymmarin:D-α-tocopherol polyethylene glycol 1000 succinate (1:1, w/w) formulation. In addition to modulating intestinal first-pass effect, Silymarin-SD formulation showed a significantly higher cumulative dissolution for 120 min compared with that of silymarin from the physical mixture (PM) of the same composition as Silymarin-SD and silymarin alone; the relative BA of silymarin-SD increased to 215% and 589% compared with silymarin-PM and silymarin alone, respectively. This could be attributed to the amorphous status of the Silymarin-SD formulation without chemical interaction with excipients, such as tween 80 and HPC. Moreover, the hepatoprotective effect of Silymarin-SD in acetaminophen-induced acute hepatotoxicity, as estimated from the alanine aminotransferase and aspartate aminotransferase values, was superior to that of silymarin. In conclusion, the increase in the dissolution rate and intestinal permeability of silymarin, and the inhibition of silymarin-glucuronidation by the Silymarin-SD formulation, prepared using tween 80 and HPC, increased its plasma concentration and resulted in a superior hepatoprotective effect compared to silymarin.
本研究旨在采用冷冻干燥法制备水飞蓟素（Silymarin-SD）固体分散体，通过抑制肠道首过效应和提高其溶解度和渗透性来增强其口服生物利用度（BA）。Silymarin-SD 制剂（即水飞蓟素：聚山梨醇酯 80：羟丙基纤维素（HPC）=1:1:3（w/w/w））通过降低水飞蓟素的外排比和抑制水飞蓟素-葡萄糖醛酸化活性，显著增加了十二指肠、空肠和回肠中水飞蓟素的渗透性，其中聚山梨醇酯 80 发挥了关键作用。结果，与水飞蓟素单独给药和水飞蓟素：D-α-生育酚聚乙二醇 1000 琥珀酸酯（1:1，w/w）制剂相比，口服 Silymarin-SD 制剂增加了大鼠血浆中水飞蓟素的浓度并降低了水飞蓟素-葡萄糖醛酸化物。除了调节肠道首过效应外，Silymarin-SD 制剂在 120 分钟时的累积溶解度明显高于相同组成的水飞蓟素物理混合物（PM）和水飞蓟素单独给药；与水飞蓟素-PM 和水飞蓟素单独给药相比，Silymarin-SD 的相对 BA 分别增加到 215%和 589%。这可能归因于 Silymarin-SD 制剂的无定形状态，没有与赋形剂（如聚山梨醇酯 80 和 HPC）发生化学相互作用。此外，Silymarin-SD 在醋氨酚诱导的急性肝毒性中的保肝作用，从丙氨酸氨基转移酶和天冬氨酸氨基转移酶的值估计，优于水飞蓟素。总之，Silymarin-SD 制剂的水飞蓟素溶出率和肠道通透性的增加，以及 Silymarin-SD 制剂对水飞蓟素-葡萄糖醛酸化的抑制作用，提高了其血浆浓度，与水飞蓟素相比具有更好的保肝作用。
