响应面分析法优化当归超临界提取物结肠定位微丸的制备工艺研究(1)
[摘要] 采用离子交联法制备当归超临界提取物丸芯，以丸芯载药量和包封率为指标，对影响载药量和包封率的多个因素进行考察，并采用Box-Behnken试验设计和响应面分析法对载药丸芯的处方进行优化，然后进行包衣工艺研究。通过体外释放研究，优选当归超临界提取物结肠定位微丸的包衣工艺及处方并评价其结肠靶向性。确定最佳的丸芯制备工艺∶3%果胶，果胶与卵磷脂比为4∶1，果胶药物比为4∶5，4%的醋酸锌溶液为交联剂，混匀温度35 ℃，交联温度35 ℃，交联时间30 min；包衣工艺∶包衣材料为尤特奇FS30D，包衣材料1.5%的柠檬酸三乙酯和聚氧乙烯脱水山梨醇单油酸酯(吐温-80)，包衣材料1.2%的单硬脂酸甘油酯，包衣增重15%。最优工艺制备的当归超临界提取物结肠定位微丸在人工胃液中2 h几乎无释放，人工小肠液中4 h释放小于20%，人工结肠液中6 h释放大于90%，说明制备的当归超临界提取物结肠定位微丸具有良好的结肠靶向性。
[关键词] 当归；超临界提取物；结肠定位；微丸；体外释放
[Abstract] To prepare pellets of supercritical fluid extraction (SFE) of Angelica Sinensis Radix by using the ionic crosslinking method， and the drug loading and encapsulation efficiency were used as the index to investigate the multiple factors which may impact the drug loading and encapsulation efficiency. Box-Behnken design and response surface analysis method were then taken to optimize the prescription of pellets and study the coating technology. Through the study on the release of pellets in vitro， an optimal coating technology and prescription of colon-specific pellets of Angelica Sinensis Radix SFE were selected and their colon targeting was evaluated. The optimal preparation parameters of pellets were determined as follows： 3% pectin；4∶1 for pectin/lecithin；4∶5 for pectin/SFE of Angelica Sinensis Radix；4% zinc acetate solution as crosslinking agent， blending temperature 35 ℃， crosslinking temperature 35 ℃， crosslinking time 30 min；coating technology： coating material Eudragit FS 30D， 1.5% triethyl citrate and polyoxyethylene sorbitan monooleate(tween-80)， 1.2% monostearin and 15% coating weight gained. The colon-specific pellets of Angelica Sinensis Radix SFE prepared with optimized conditions were almost not released in simulated gastric fluid in 2 h， released less than 20% in simulated intestine fluid in 4 h， and released more than 90% in simulated colon fluid in 6 h， indicating that the colon-specific pellets of Angelica Sinensis Radix SFE had an excellent colon targeting property.
[Key words] Angelicae Sinensis Radix；supercritical fluid extract；colon-specific；pellets；release in vitro
doi：10.4268/cjcmm20161312
当归为伞形科植物当归Angelica sinensis(Oliv.)Diels的干燥根，有补血活血，调经止痛，润燥滑肠的功效[1]。当归的化学成分主要为挥发油和水溶性成分，现代药理研究证明当归及其有效成分具有抗炎、抗氧化、抗肿瘤等作用[2-3]。其超临界提取物中成分较多，包括内酯类、有机酸类等，其中藁本内酯含量最高，可达50%～75%[4]。
课题组前期研究发现当归超临界提取物在细胞模型上有较好的抗炎与抗氧化作用[5]；动物模型上证明其对炎症相关的结直肠癌有一定的化学预防作用[6-7]，但藁本内酯性质不稳定易分解，在消化道及肝脏内的代谢较多，生物利用度低，很大程度上影响其药效作用的发挥[7]。口服结肠定位制剂作为新型释药系统，是将药物口服后，在上消化道不释放，待药物输送至人体回盲部位后开始释放，从而在大肠发挥局部或全身治疗作用[8]。将当归超临界提取物制成口服结肠定位微丸，以期使药物口服后在结肠释放，使其发挥局部和全身的作用，提高对结直肠癌的化学预防效果。果胶作为一种只能被结肠内肠道菌群降解的天然高分子多糖，具有安全无毒、生物相容性好、体内可降解等优点，是一种理想的口服结肠定位给药载体[9]。低酯果胶可与二价阳离子交联，形成类似于“蛋壳结构”凝胶将药物包载，故本研究以低脂果胶为材料，采用离子交联法制备当归超临界提取物丸芯，通过对影响丸芯载药量和包封率的因素进行考察，确定主要影响因素，采用Box-Behnken试验设计，以载药量和包封率为指标对载药丸芯的处方进行了优化，并进行包衣。通过对结肠定位微丸的体外释放研究，优选当归超临界提取物结肠定位微丸的制备和包衣工艺并评价其结肠靶向性。 (茹庆国 彭宇 马书伟 张庆 谭鹏 吴清)
[关键词] 当归；超临界提取物；结肠定位；微丸；体外释放
[Abstract] To prepare pellets of supercritical fluid extraction (SFE) of Angelica Sinensis Radix by using the ionic crosslinking method， and the drug loading and encapsulation efficiency were used as the index to investigate the multiple factors which may impact the drug loading and encapsulation efficiency. Box-Behnken design and response surface analysis method were then taken to optimize the prescription of pellets and study the coating technology. Through the study on the release of pellets in vitro， an optimal coating technology and prescription of colon-specific pellets of Angelica Sinensis Radix SFE were selected and their colon targeting was evaluated. The optimal preparation parameters of pellets were determined as follows： 3% pectin；4∶1 for pectin/lecithin；4∶5 for pectin/SFE of Angelica Sinensis Radix；4% zinc acetate solution as crosslinking agent， blending temperature 35 ℃， crosslinking temperature 35 ℃， crosslinking time 30 min；coating technology： coating material Eudragit FS 30D， 1.5% triethyl citrate and polyoxyethylene sorbitan monooleate(tween-80)， 1.2% monostearin and 15% coating weight gained. The colon-specific pellets of Angelica Sinensis Radix SFE prepared with optimized conditions were almost not released in simulated gastric fluid in 2 h， released less than 20% in simulated intestine fluid in 4 h， and released more than 90% in simulated colon fluid in 6 h， indicating that the colon-specific pellets of Angelica Sinensis Radix SFE had an excellent colon targeting property.
[Key words] Angelicae Sinensis Radix；supercritical fluid extract；colon-specific；pellets；release in vitro
doi：10.4268/cjcmm20161312
当归为伞形科植物当归Angelica sinensis(Oliv.)Diels的干燥根，有补血活血，调经止痛，润燥滑肠的功效[1]。当归的化学成分主要为挥发油和水溶性成分，现代药理研究证明当归及其有效成分具有抗炎、抗氧化、抗肿瘤等作用[2-3]。其超临界提取物中成分较多，包括内酯类、有机酸类等，其中藁本内酯含量最高，可达50%～75%[4]。
课题组前期研究发现当归超临界提取物在细胞模型上有较好的抗炎与抗氧化作用[5]；动物模型上证明其对炎症相关的结直肠癌有一定的化学预防作用[6-7]，但藁本内酯性质不稳定易分解，在消化道及肝脏内的代谢较多，生物利用度低，很大程度上影响其药效作用的发挥[7]。口服结肠定位制剂作为新型释药系统，是将药物口服后，在上消化道不释放，待药物输送至人体回盲部位后开始释放，从而在大肠发挥局部或全身治疗作用[8]。将当归超临界提取物制成口服结肠定位微丸，以期使药物口服后在结肠释放，使其发挥局部和全身的作用，提高对结直肠癌的化学预防效果。果胶作为一种只能被结肠内肠道菌群降解的天然高分子多糖，具有安全无毒、生物相容性好、体内可降解等优点，是一种理想的口服结肠定位给药载体[9]。低酯果胶可与二价阳离子交联，形成类似于“蛋壳结构”凝胶将药物包载，故本研究以低脂果胶为材料，采用离子交联法制备当归超临界提取物丸芯，通过对影响丸芯载药量和包封率的因素进行考察，确定主要影响因素，采用Box-Behnken试验设计，以载药量和包封率为指标对载药丸芯的处方进行了优化，并进行包衣。通过对结肠定位微丸的体外释放研究，优选当归超临界提取物结肠定位微丸的制备和包衣工艺并评价其结肠靶向性。 (茹庆国 彭宇 马书伟 张庆 谭鹏 吴清)