川芎嗪醇质体控释贴片的研究
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摘要
背景：川芎嗪是中药川芎中的主要活性生物碱,具有保护心肌细胞,扩张冠状动脉,抵抗血小板粘附聚集,抑制血栓形成,抗动脉粥样硬化,清除氧自由基等多种药理作用。川芎嗪对心脏具有良好的生物活性,临床上主要用于治疗冠心病等。纳米脂质体技术作为一种药物载体技术,具有适合体内降解、无毒性和无免疫原性、可包裹水、脂溶性两种类型药物、保护被包封药物、减少用药剂量及可修饰产生主动靶向性等诸多优良特性。而新一代脂质体—醇质体,由于其具备良好的变形性,更有利于通过表皮屏障,能进入皮肤更深层,渗透性能更佳。
目的：通过不同膜材、处方和工艺的优选,研制具有良好透皮吸收性能的醇质体。同时,以制备治疗冠心病心绞痛的川芎嗪醇质体控释型皮肤贴片为研究切入点,研制剂型稳定,包封率、释放度以及经皮吸收性能良好的川芎嗪控释皮肤贴片,最终形成制备中药经皮全身给药制剂的新方法。
方法：以包封率为指标,考察川芎嗪醇质体制备过程中磷脂浓度、乙醇含量、超声时间以及柔性辅料用量的影响,并通过正交设计实验,对川芎嗪醇质体的制备工艺和处方进行筛选,确定最佳处方。以丙烯酸树脂为主要组分,加入琥珀酸作为交联剂、柠檬酸三乙酯作为增塑剂,通过正交设计实验,对川芎嗪醇质体贴剂的处方进行优化。采用高效液相色谱法对制备的川芎嗪醇质体透皮贴剂进行体外透皮试验以及体外释放度测定,考察其体外透皮率以及体外释药性能。药动学实验中测定A组(灌胃给药)、B组(醇质体透皮给药)和C组(常规透皮给药)大鼠在用药后各组织的药时曲线,采用药动学3p97软件研究川芎嗪醇质体在大鼠体内的药动学特征及相对生物利用度。药理实验中观察川芎嗪醇质体透皮贴对缺血心肌以及心肌缺血后再灌注损伤的保护作用。
结果：川芎嗪醇质体的最佳处方为磷脂浓度为1.00 g/100 ml,乙醇含量为45%(v/v),超声时间为5 min,以优化工艺制得的川芎嗪醇质体粒径分布均匀,平均粒径为(78.71±1.23)nm,平均包封率为(86.42±1.50)%。川芎嗪醇质体贴剂最优处方为丙烯酸树脂0.4g、柠檬酸三乙酯0.23g、琥珀酸0.054 g,川芎嗪醇质体混悬液和氮酮的含量分别为10%和5%。川芎嗪醇质体贴剂体外透皮试验结果显示24小时药物累积透皮量达183±18μg·cm-2,其体外释放度曲线24 h内符合Higuchi方程,具有显著的控释效果。药动学实验中,B组心脏的AUC值是A组的2.52倍,而B组肝脏的AUC值只有A组的1.57倍,提示川芎嗪醇质体增强了药物对心脏的作用,而对肝脏的毒性作用相对减弱,其相对生物利用度达到209.45%。而C组的AUC值与A组相比差别不大,说明其透皮效果较差,相对生物利用度只有98.63%。贴剂对缺血心肌保护作用实验结果表明,药物贴剂组的血液流变学指数较缺血对照组有显著性差异(P<0.01),说明川芎嗪醇质体贴剂对实验性冠状动脉痉挛所致心肌缺血的心肌细胞具有保护作用。而贴剂对心肌缺血后再灌注损伤的保护作用实验结果表明,贴剂组对心脏的复灌性心律失常无明显改善,但能显著缩小随后长时间缺血所引起的心肌梗塞范围。
结论：川芎嗪醇质体贴剂透皮效果好,有显著控释作用,相对生物利用度增加,对缺血心肌和缺血后再灌注损伤心肌均有保护作用。
Backgrounds:Ligustrazine is a primary active alkaloid of Chinese medicine Szechwan Lovage Rhizome, which has many pharmacological actions such as protecting myocardium cells, broadening coronary artery, inhibiting platelet adhesion and aggregation, inhibiting thrombosis, anti-atherosclerosis and removing oxygen-derived free radicals etc, and using for coronary heart disease in clinic. Nanoliposomes as a drug carrier, has many good properties such as degradation in vivo, avirulent, non-immunogenicity, ability to encapsulate drug of water solubility and liposolubility, protecting encapsulated drug, reduce drug dosage and active targeting after modification. And ethosomes, novel liposomes, has better deformability, more advantage to through epidermis barrier into deeper layer of skin, and better permeability.
Objective:This study is to prepare Ligustrazine ethosomes for coronary heart disease with good permeability by optimizing different formulations and technology parameters, to prepare controlled release delivery system of Ligustrazine ethosomes dermal patch with stable formulations, better encapsulating efficient, release rate and permeability, and to research novel preparation methods of transdermal drug delivery system for Chinese medicine.
Methods:Encapsulating efficiency as index, the effect of phospholipids concentration, ethanol content, sonication time and flexible adjuvants dosage on Ligustrazine ethosomes during preparation was studied. The preparation technology and formulations was optimized. The patch formulations was optimized by orthogonal design which used acrylic resin as major composition, in addition to succinic acid as crosslinking agent and triethyl citrate as plasticizer. Transdermal experiment and release rate in vitro of The Ligustrazine ethosomes patch was detected by high-performance liquid chromatography (HPLC). The drug concentration-time curve was detected for group A (intragastric administration for rats), group B (transdermal delivery of Ligustrazine ethosomes) and group C (common transdermal delivery), and the pharmacokinetics characteristics and relative bioavailability of Ligustrazine ethosomes on rats was analyzed by pharmacokinetics software 3p97. The protection effect of Ligustrazine ethosomes patch for ischemia myocardium and reperfusion injury after ischemia myocardium was observed.
Results:The best formulations for Ligustrazine ethosomes were 10 g/L phospholipids concentration,45%(v/v) ethanol content and 5 min sonication time, and Ligustrazine ethosomes prepared according to this formulations was with uniform size distribution, mean size (78.71±1.23) nm, mean encapsulating efficiency (86.42±1.50)%. The best formulations of Ligustrazine ethosomes patch were 0.4 g acrylic resin,0.23 g succinic acid and 0.054 g triethyl citrate,10% Ligustrazine ethosomes and 5% azone. The 24h drug accumulation permeation quantity of the Ligustrazine ethosomes patch was 183±18μg-cm-2, the release profile in vitro was in line with Higuchi formulation, and it had significant controlled release effect in 24h. AUC value on heart of group B was2.52 times of that of group A, AUC value on liver of group B was 1.57 times of that of group A, and the relative bioavailability was 209.45%. This revealed that Ligustrazine ethosomes enhanced the drug efficacy for heart and relatively relieved the liver toxicity. And AUC value of group C and A was not significantly different, the relative bioavailability was 98.63%, this revealed that transdermal effect was comparatively poor. The results of protection experiment showed that Ligustrazine ethosomes patch had protection effect for cells of myocardial ischemia by experimental coronarospasm because there were significant difference between the hemorheology index of Ligustrazine ethosomes patch group and control group (P<0.01). And in the Ligustrazine ethosomes patch group, it was not obviously improved for arrhythmia induced by myocardium reperfusion, but could diminish significantly the myocardial infarction range caused by following long time ischemia.
Conclusions:Ligustrazine ethosomes patch has good transdermal effect, significant controlled release action, increased relative bioavailability, and protection effect for ischemia myocardium and reperfusion injury after ischemia myocardium.
目的：通过不同膜材、处方和工艺的优选,研制具有良好透皮吸收性能的醇质体。同时,以制备治疗冠心病心绞痛的川芎嗪醇质体控释型皮肤贴片为研究切入点,研制剂型稳定,包封率、释放度以及经皮吸收性能良好的川芎嗪控释皮肤贴片,最终形成制备中药经皮全身给药制剂的新方法。
方法：以包封率为指标,考察川芎嗪醇质体制备过程中磷脂浓度、乙醇含量、超声时间以及柔性辅料用量的影响,并通过正交设计实验,对川芎嗪醇质体的制备工艺和处方进行筛选,确定最佳处方。以丙烯酸树脂为主要组分,加入琥珀酸作为交联剂、柠檬酸三乙酯作为增塑剂,通过正交设计实验,对川芎嗪醇质体贴剂的处方进行优化。采用高效液相色谱法对制备的川芎嗪醇质体透皮贴剂进行体外透皮试验以及体外释放度测定,考察其体外透皮率以及体外释药性能。药动学实验中测定A组(灌胃给药)、B组(醇质体透皮给药)和C组(常规透皮给药)大鼠在用药后各组织的药时曲线,采用药动学3p97软件研究川芎嗪醇质体在大鼠体内的药动学特征及相对生物利用度。药理实验中观察川芎嗪醇质体透皮贴对缺血心肌以及心肌缺血后再灌注损伤的保护作用。
结果：川芎嗪醇质体的最佳处方为磷脂浓度为1.00 g/100 ml,乙醇含量为45%(v/v),超声时间为5 min,以优化工艺制得的川芎嗪醇质体粒径分布均匀,平均粒径为(78.71±1.23)nm,平均包封率为(86.42±1.50)%。川芎嗪醇质体贴剂最优处方为丙烯酸树脂0.4g、柠檬酸三乙酯0.23g、琥珀酸0.054 g,川芎嗪醇质体混悬液和氮酮的含量分别为10%和5%。川芎嗪醇质体贴剂体外透皮试验结果显示24小时药物累积透皮量达183±18μg·cm-2,其体外释放度曲线24 h内符合Higuchi方程,具有显著的控释效果。药动学实验中,B组心脏的AUC值是A组的2.52倍,而B组肝脏的AUC值只有A组的1.57倍,提示川芎嗪醇质体增强了药物对心脏的作用,而对肝脏的毒性作用相对减弱,其相对生物利用度达到209.45%。而C组的AUC值与A组相比差别不大,说明其透皮效果较差,相对生物利用度只有98.63%。贴剂对缺血心肌保护作用实验结果表明,药物贴剂组的血液流变学指数较缺血对照组有显著性差异(P<0.01),说明川芎嗪醇质体贴剂对实验性冠状动脉痉挛所致心肌缺血的心肌细胞具有保护作用。而贴剂对心肌缺血后再灌注损伤的保护作用实验结果表明,贴剂组对心脏的复灌性心律失常无明显改善,但能显著缩小随后长时间缺血所引起的心肌梗塞范围。
结论：川芎嗪醇质体贴剂透皮效果好,有显著控释作用,相对生物利用度增加,对缺血心肌和缺血后再灌注损伤心肌均有保护作用。
Backgrounds:Ligustrazine is a primary active alkaloid of Chinese medicine Szechwan Lovage Rhizome, which has many pharmacological actions such as protecting myocardium cells, broadening coronary artery, inhibiting platelet adhesion and aggregation, inhibiting thrombosis, anti-atherosclerosis and removing oxygen-derived free radicals etc, and using for coronary heart disease in clinic. Nanoliposomes as a drug carrier, has many good properties such as degradation in vivo, avirulent, non-immunogenicity, ability to encapsulate drug of water solubility and liposolubility, protecting encapsulated drug, reduce drug dosage and active targeting after modification. And ethosomes, novel liposomes, has better deformability, more advantage to through epidermis barrier into deeper layer of skin, and better permeability.
Objective:This study is to prepare Ligustrazine ethosomes for coronary heart disease with good permeability by optimizing different formulations and technology parameters, to prepare controlled release delivery system of Ligustrazine ethosomes dermal patch with stable formulations, better encapsulating efficient, release rate and permeability, and to research novel preparation methods of transdermal drug delivery system for Chinese medicine.
Methods:Encapsulating efficiency as index, the effect of phospholipids concentration, ethanol content, sonication time and flexible adjuvants dosage on Ligustrazine ethosomes during preparation was studied. The preparation technology and formulations was optimized. The patch formulations was optimized by orthogonal design which used acrylic resin as major composition, in addition to succinic acid as crosslinking agent and triethyl citrate as plasticizer. Transdermal experiment and release rate in vitro of The Ligustrazine ethosomes patch was detected by high-performance liquid chromatography (HPLC). The drug concentration-time curve was detected for group A (intragastric administration for rats), group B (transdermal delivery of Ligustrazine ethosomes) and group C (common transdermal delivery), and the pharmacokinetics characteristics and relative bioavailability of Ligustrazine ethosomes on rats was analyzed by pharmacokinetics software 3p97. The protection effect of Ligustrazine ethosomes patch for ischemia myocardium and reperfusion injury after ischemia myocardium was observed.
Results:The best formulations for Ligustrazine ethosomes were 10 g/L phospholipids concentration,45%(v/v) ethanol content and 5 min sonication time, and Ligustrazine ethosomes prepared according to this formulations was with uniform size distribution, mean size (78.71±1.23) nm, mean encapsulating efficiency (86.42±1.50)%. The best formulations of Ligustrazine ethosomes patch were 0.4 g acrylic resin,0.23 g succinic acid and 0.054 g triethyl citrate,10% Ligustrazine ethosomes and 5% azone. The 24h drug accumulation permeation quantity of the Ligustrazine ethosomes patch was 183±18μg-cm-2, the release profile in vitro was in line with Higuchi formulation, and it had significant controlled release effect in 24h. AUC value on heart of group B was2.52 times of that of group A, AUC value on liver of group B was 1.57 times of that of group A, and the relative bioavailability was 209.45%. This revealed that Ligustrazine ethosomes enhanced the drug efficacy for heart and relatively relieved the liver toxicity. And AUC value of group C and A was not significantly different, the relative bioavailability was 98.63%, this revealed that transdermal effect was comparatively poor. The results of protection experiment showed that Ligustrazine ethosomes patch had protection effect for cells of myocardial ischemia by experimental coronarospasm because there were significant difference between the hemorheology index of Ligustrazine ethosomes patch group and control group (P<0.01). And in the Ligustrazine ethosomes patch group, it was not obviously improved for arrhythmia induced by myocardium reperfusion, but could diminish significantly the myocardial infarction range caused by following long time ischemia.
Conclusions:Ligustrazine ethosomes patch has good transdermal effect, significant controlled release action, increased relative bioavailability, and protection effect for ischemia myocardium and reperfusion injury after ischemia myocardium.
引文
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