自微乳化释药系统对银杏内酯B在视网膜内药代动力学参数的影响

Effect of ginkgolide B-loaded self microemulsifying drug deliver system on pharmacokinetics of ginkgolide B in retina

背景银杏内酯B（GB）具有明确的神经保护和抗凋亡作用，可以有效拮抗视网膜内感光细胞的凋亡，达到治疗视网膜变性类疾病的目的，但GB的高疏水性和低生物利用度限制了其临床应用。自微乳化释药系统（SMEDDS）能有效提高难溶性药物的溶出度和生物利用度，因此可能提高GB在视网膜中的生物利用度。目的研究自制GB-SMEDDS灌胃后在sD大鼠视网膜内的药代动力学及药时变化。方法采用随机数字表法将80只SD大鼠分为GB混悬液组和GB-SMEDDS组2个组，每组40只，分别给予40mg／kg自制质量分数2．5％GB-SMEDDS或GB混悬液（质量分数0．1％DMSO溶解）灌胃，并于给药后15、30、45min和1、2、4、8、12h分别处死5只大鼠，解剖显微镜下分离大鼠视网膜，制备大鼠视网膜上清液，经高效液相-电喷雾离子-质谱联用（HPLC-ESI-MS）法检测GB的质量浓度，并与标准曲线对比换算，药代动力学参数采用实用药物动力学程序3p87中的统计矩方法计算，计算出视网膜中的最大药物质量分数（Cmax，mg／g）、药物达峰时间（Tmax，h）、清除率（Ke／h）、吸收半衰期（t。）和药时曲线下面积[AUC0-∞mg／（g·h）]。结果GB在1～32mg／L时线性关系良好，线性回归方程为Y=0．0732X＋0．056（r=0．992）。GB-SMEDDS组和GB混悬液组大鼠灌胃后有着相似的药时曲线，但是除了给药后15min视网膜中的药物质量分数两者一致外，其他各个时间点GB-SMEDDS组视网膜内药物质量分数均高于GB混悬液组。两组大鼠视网膜中Cmax分别为（15．83±1．84）mg／g和（2．65±0．10）mg／g，AUC0-∞分别为（15．30±0．11）mg／（g·h）和（6．42±0．19）ing／（g·h）。结论HPLC-ESI-MS具有快速、准确、灵敏度高的特点，适合GB制剂在SD大鼠视网膜中药代动力学的研究。SMEDDS可以显著提高GB在视网膜中的含量，可能提高其生物利用度。

Background Ginkgolide B （GB） has been proved to have neuroprotective and anti-apoptotic effects and can effectively inhibit apoptosis of retinal photoreceptor cells. But the high hydrophobic feature and low bioavailability of GB limit its clinical application. Self mieroemulsifying drug delivery system （SMEDDS） can effectively improve the infusibility drug dissolution and bioavailability in the retina. Objective This study was to investigate the pharmacokineties and drug-time change of GB-loaded SMEDDS in retina. Methods Eighty SD rats were randomized into 2 groups,2.5% GB（40 mg/kg） of SMEDDS or GB suspension（0. 1% DMSO dissolve） were gastrically given respectively in two groups. The rats were sacrificed and retinas were isolated 15,30,45 minutes and 1 hour,2,4, 8, 12 hours to prepare the retinal suspension. The content of GB in retina was assayed with high performance liquid ehromatography-eleetrospray ionization-mass spectrum （HPLC-ESI-MS） and contrasted with standard curve. Practical drug dynamics program 3p87 was used to detect the pharmacokinetics parameters. The maximal content （ Cmax mg/g） , time to peak （ T h ） , clearance ratio （ Ke/h ） , high-life period （ tl/2 ） and area under the concentration-time curve（AUC0-∞ ,mg/（g · h）） of GB in various time points in retina after a single oral dose were calculated and compared between two groups. Results The standard curve was obtained over the concentration range of 1 - 32 mg/L with a linear regression equation, Y = 0. 0732X ＋ 0. 056 （ r = 0. 992 ）. A similar content-time curve was seen between GB suspension group and GB-SMEDDS group. The GB content was higher in GB-SMEDDS group than that in GB suspension group from 30 minutes through 12 hours after administration of drugs. The Cmax of GB-SMEDDS group and GB suspension group were （ 15.83 ±1.84 ） mg/g and （ 2. 65 ±0. 10） mg/g, the AUC0-∞ were（15.30±0.11）mg/（g · h）and（6.42±0. 19） mg/（g · h）. Conclusions HPLC-ESI-MS is proved to be a rapid,accurate,sensitive and suitable method for pharmocokinetic study of GB. SMEDDS can raise the concent of GB in retina, and it probably improve the bioavailability of GB.