莲子心微囊的稳定性及其释药规律研究
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摘要
莲子心制剂,文献报道的多为注射液,但其注射液性质不稳定。而微囊作为药物载体,有提高药物稳定性、缓释或控释作用、靶向性能和生物利用度高等许多优于传统剂型的特点,研制莲子心微囊,较以中药单一成分进行微囊的研究,更能体现中药多层次多靶点的作用特点,并能有效地提高药物制剂的稳定性。
前期已进行了莲子心中总生物碱的半仿生提取工艺研究、莲子心微囊的制备工艺研究和莲子心微囊抗多种实验性抗心率失常作用的药效研究。
本文是在前期研究的基础上,进行的进一步研究,探讨了莲子心总碱微囊化后的稳定性,并考察了莲子心微囊的体内外释药规律。
目的:考察莲子心微囊的稳定性;考察以明胶作为囊材的莲子心微囊的体外溶出特点;通过对豚鼠的心率失常模型进行给药后的心电图监测,确定微囊的最佳给药剂量;研究莲子心微囊在家兔体内的血药浓度变化。
方法:参照文献进行莲子心总碱的提取,并制备莲子心微囊,运用留样观察法进行稳定性考察;模拟人体体内环境,以人工胃液作为溶出介质,用紫外分光光度法测定莲子心微囊不同时间点的生物碱含量,得出微囊的体外释放度;采用哇巴因诱导心率失常的豚鼠模型,将豚鼠分成5个等级的剂量组,每个剂量组连续给药五天,末次给药30min后进行心电图监测,从而比较给药剂量和心率失常的量效关系,得出最佳的给药剂量;给家兔灌胃莲子心微囊后,采用反相高效液相色谱法检测各时间点血浆中的莲心碱的浓度变化,用DAS(drug and statistics)程序拟合房室模型并计算药代动力学参数。
结果:留样观察法考核一年,每个月对微囊的莲子心总碱含量进行测定,其含量基本不变;莲子心微囊的体外释放符合Higuchui方程释药模式;通过豚鼠的心电图监测,各个剂量组的豚鼠心率失常出现时间延长,失常持续时间缩短,恢复正常持续的时间延长,均呈剂量依赖性改善作用,得到莲子心微囊的最佳给药剂量为100mg/100g:以莲子心微囊10g.kg~(-1)的剂量灌胃,其在家兔体内的释药规律符合开放性二室模型,其主要药物动力学参数为:t_(1/2α)=1.172h,t_(1/2β)=17.676h,AUC=16.754mg/L*h,CL=6.254L/h/kg,Cmax=2.678mg/L。
结论:莲子心总碱经过微囊化后,可增加其稳定性;不同粒径的微囊的释放趋势基本一致;莲子心微囊的抗实验性心率失常作用与剂量成依赖性关系;莲子心微囊在家兔体内的释药规律符合开放性二室模型。
Most preparation of Plumula Nelumbinis recorded are injection.But the quality of the injection of Plumula Nelumbinis is not stabilititated.And that,as the carrier of medicament,the Microcapsules can improve the stability of medicament,slow-released,or controlled-released effect.And the target function and biological availability are better than the traditional dosage form.To study the Plumula Nelumbinis Microcapsules,it can personification the charateristic of multistrata and multitarget of Chinese Medicine,and it can efficiently elevate the stability of pharmaceutical preparation. @
The study contents before include:1)the optimization of the extract technical of Plumula Nelunbinis.2)the optimization of the preparation technical of Plumula Nelunbinis Microcapsules.3)the study of anti-arrhythmia of Plumula Nelunbinis Microcapsules. @
We study the Plumula Nelunbinis Microcapsules in the base of the protophase study.We approach the stability of TAL(total alkaloids of lianzixin)after microencapsulation,and to study the method of drug-released of Plumula Nelunbinis Microcapsules. @
Objective: @
To study the stability of TAL(total alkaloids of lianzixin)after microencapsulation;To study the dissolution rate in vitro of Plumula Nelumbinis microcapsules which were prepared with gelatin as coating material: To do electrocardiogram monitoring on guinea pigs after administration to definite the optimal dosage of Plumula Nelumbinis Microcapsules;To study the transmutation of blood plasma concentration of drugs in rabbits after administration with Plumula Nelumbinis Microcapsules. @
Method: @
To use remaining sample observation method to consider;The drug release was determined by ultra-violet spectrophotometry;The arrhythmia models were induced by ouabain(in guinea pig),60 model guinea pigs were divided into five dosage groups,each group were preventively administered with drugs for 5 days, and the indexes of experiment were determined and evaluated 30min after the final administration.Thus to definite the dose-effect relationship and optimal dosage;after intragastric administration on rabbits,the plasma concentration of drugs in each time point was detected by using reversed phase high performance liquid chromatography method and the data was dealt with drug and statistics program to calculate the pharmacokinetics parameters and select apartment model. @
Result: @
Using remaining sample observation method to check every month for one year, the content of TAL in the microcapsules remain invariably;The drug release from the microcapsules followed Higuchui model kinetics;To do electrocardiogram monitoring on guinea pigs after administration,each group showed that delayed occurrence of arrhythmia,shortened duration of arrhythmia, prolonged duration with normal cardiac rhythm were improved by dose dependent. The best dose of Plumula Nelumbinis Microcapsules is 100mg/100g; administrating rabbits with Plumula Nelumbinis Microcapsules,the time-concentration curve of TAL intravenous administration corresponded to the model of two apartments.The main pharmacokinetics parameters were: t_(1/2α)=1.172h,t_(1、2β)=17.676h,AUC=16.754mg/L*h,CL=6.254L/h/kg,Cmax=2.678 mg/L. @
Conclusion: @
The stability of the TAL in the microcapsule is increased after Microeacapsulation:the Microcapsules of diffent diameter have the same tendency of release;The anti-arrhythmic effects of Plumula Nelumbinis Microcapsules is dependenced on the dose:the time-concentration curve of Plumula Nelumbinis Microcapsules in rabbits corresponded to the model of two apartments.
前期已进行了莲子心中总生物碱的半仿生提取工艺研究、莲子心微囊的制备工艺研究和莲子心微囊抗多种实验性抗心率失常作用的药效研究。
本文是在前期研究的基础上,进行的进一步研究,探讨了莲子心总碱微囊化后的稳定性,并考察了莲子心微囊的体内外释药规律。
目的:考察莲子心微囊的稳定性;考察以明胶作为囊材的莲子心微囊的体外溶出特点;通过对豚鼠的心率失常模型进行给药后的心电图监测,确定微囊的最佳给药剂量;研究莲子心微囊在家兔体内的血药浓度变化。
方法:参照文献进行莲子心总碱的提取,并制备莲子心微囊,运用留样观察法进行稳定性考察;模拟人体体内环境,以人工胃液作为溶出介质,用紫外分光光度法测定莲子心微囊不同时间点的生物碱含量,得出微囊的体外释放度;采用哇巴因诱导心率失常的豚鼠模型,将豚鼠分成5个等级的剂量组,每个剂量组连续给药五天,末次给药30min后进行心电图监测,从而比较给药剂量和心率失常的量效关系,得出最佳的给药剂量;给家兔灌胃莲子心微囊后,采用反相高效液相色谱法检测各时间点血浆中的莲心碱的浓度变化,用DAS(drug and statistics)程序拟合房室模型并计算药代动力学参数。
结果:留样观察法考核一年,每个月对微囊的莲子心总碱含量进行测定,其含量基本不变;莲子心微囊的体外释放符合Higuchui方程释药模式;通过豚鼠的心电图监测,各个剂量组的豚鼠心率失常出现时间延长,失常持续时间缩短,恢复正常持续的时间延长,均呈剂量依赖性改善作用,得到莲子心微囊的最佳给药剂量为100mg/100g:以莲子心微囊10g.kg~(-1)的剂量灌胃,其在家兔体内的释药规律符合开放性二室模型,其主要药物动力学参数为:t_(1/2α)=1.172h,t_(1/2β)=17.676h,AUC=16.754mg/L*h,CL=6.254L/h/kg,Cmax=2.678mg/L。
结论:莲子心总碱经过微囊化后,可增加其稳定性;不同粒径的微囊的释放趋势基本一致;莲子心微囊的抗实验性心率失常作用与剂量成依赖性关系;莲子心微囊在家兔体内的释药规律符合开放性二室模型。
Most preparation of Plumula Nelumbinis recorded are injection.But the quality of the injection of Plumula Nelumbinis is not stabilititated.And that,as the carrier of medicament,the Microcapsules can improve the stability of medicament,slow-released,or controlled-released effect.And the target function and biological availability are better than the traditional dosage form.To study the Plumula Nelumbinis Microcapsules,it can personification the charateristic of multistrata and multitarget of Chinese Medicine,and it can efficiently elevate the stability of pharmaceutical preparation. @
The study contents before include:1)the optimization of the extract technical of Plumula Nelunbinis.2)the optimization of the preparation technical of Plumula Nelunbinis Microcapsules.3)the study of anti-arrhythmia of Plumula Nelunbinis Microcapsules. @
We study the Plumula Nelunbinis Microcapsules in the base of the protophase study.We approach the stability of TAL(total alkaloids of lianzixin)after microencapsulation,and to study the method of drug-released of Plumula Nelunbinis Microcapsules. @
Objective: @
To study the stability of TAL(total alkaloids of lianzixin)after microencapsulation;To study the dissolution rate in vitro of Plumula Nelumbinis microcapsules which were prepared with gelatin as coating material: To do electrocardiogram monitoring on guinea pigs after administration to definite the optimal dosage of Plumula Nelumbinis Microcapsules;To study the transmutation of blood plasma concentration of drugs in rabbits after administration with Plumula Nelumbinis Microcapsules. @
Method: @
To use remaining sample observation method to consider;The drug release was determined by ultra-violet spectrophotometry;The arrhythmia models were induced by ouabain(in guinea pig),60 model guinea pigs were divided into five dosage groups,each group were preventively administered with drugs for 5 days, and the indexes of experiment were determined and evaluated 30min after the final administration.Thus to definite the dose-effect relationship and optimal dosage;after intragastric administration on rabbits,the plasma concentration of drugs in each time point was detected by using reversed phase high performance liquid chromatography method and the data was dealt with drug and statistics program to calculate the pharmacokinetics parameters and select apartment model. @
Result: @
Using remaining sample observation method to check every month for one year, the content of TAL in the microcapsules remain invariably;The drug release from the microcapsules followed Higuchui model kinetics;To do electrocardiogram monitoring on guinea pigs after administration,each group showed that delayed occurrence of arrhythmia,shortened duration of arrhythmia, prolonged duration with normal cardiac rhythm were improved by dose dependent. The best dose of Plumula Nelumbinis Microcapsules is 100mg/100g; administrating rabbits with Plumula Nelumbinis Microcapsules,the time-concentration curve of TAL intravenous administration corresponded to the model of two apartments.The main pharmacokinetics parameters were: t_(1/2α)=1.172h,t_(1、2β)=17.676h,AUC=16.754mg/L*h,CL=6.254L/h/kg,Cmax=2.678 mg/L. @
Conclusion: @
The stability of the TAL in the microcapsule is increased after Microeacapsulation:the Microcapsules of diffent diameter have the same tendency of release;The anti-arrhythmic effects of Plumula Nelumbinis Microcapsules is dependenced on the dose:the time-concentration curve of Plumula Nelumbinis Microcapsules in rabbits corresponded to the model of two apartments.
引文
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