以生物药剂学为指导的麻黄汤剂型改进的探索
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摘要
目的本文以麻黄汤为模型方药,根据自乳化药物传递系统(SEDDS)的定义,以方中油脂性药物中提取出来的油为油相,其它提取成分为药物或赋形剂,加入表面活性剂制得自乳化制剂,加水溶散后将其还原成汤剂的状态,并比较两者粒径大小。然后通过采用现代分析技术及动物在体小肠循环的方法,对麻黄汤及其自乳化制剂中的指标成分的吸收情况进行比较,考察两种制剂吸收的异同与粒径大小的相关性。本文是对中药复方汤剂剂型改进的初步性探索,以期能为中药复方剂型改进提供新的研究方法与思路。
方法采用分两步提取的方法提取药材中的脂溶性成分和水溶性成分,以性状与粒径大小为考察指标,制备麻黄汤自乳化制剂;结合显微镜及粒度测定两种方法测定麻黄汤、麻黄汤自乳化制剂、麻黄汤未加乳化剂的制剂及市售单方颗粒水溶散后液体中微粒粒径;以大鼠在体肠循环的方法研究制剂的吸收情况,HPLC-电化学检测方法测定肠循环液中麻黄碱与伪麻黄碱的含量,RP-HPLC法测定桂皮醛含量,HPLC-电化学检测方法进行指纹图谱研究,比较麻黄汤、麻黄汤自乳化制剂、麻黄汤未加乳化剂的制剂及市售单方颗粒制得的麻黄汤在大鼠小肠的吸收情况。
结果药材提取结果:每克麻黄药材约得0.375克水提物:每克桂枝药材约得0.029克乙醚提取物及0.060克水提物;每克杏仁药材约得0.195克植物油及0.077克水提取物;每克甘草药材约得0.478克水提物。
自乳化制剂处方研究为:乳化剂的用量约为40%且泊洛沙姆和卵磷脂联合使用(比例为3∶1)时,乳化效果最好,显微镜下观察,产生的乳滴粒径较小,为(3.51±2.46)μm,与汤剂粒径(3.86±2.73)μm较为接近。
以电化学检测的反相HPLC定量测定麻黄碱和伪麻黄碱,检测灵敏度高,定量准确,是一个可行的方法;以紫外检测的反相HPLC定量测定桂皮醛,检测灵敏度高,定量准确,样品室温下稳定性好。
各制剂粒径大小及其大鼠在体肠吸收结果表明,药物粒径的大小可影响药物的吸收,当药物的粒径大于某一粒径时,就会对药物的吸收产生影响。吸收结果表明,汤剂中的麻黄碱和伪麻黄碱吸收率最大,其次为自制自乳化制剂,未加乳化剂的物理混合制剂相对最慢。这与其粒径大小相一致。桂皮醛的吸收以其含量最高的制剂中的吸收为最快最多,与粒径大小未表现出相关性,可能是由于其粒径还未超过对其吸收产生影响的粒径大小。
指纹图谱研究结果表明,甘草苷、麻黄碱及伪麻黄碱给药70分钟吸收量较多,但70分钟以后吸收量较小;苦杏仁苷给药前后峰高相当,若不计体积变化,其吸收很少。汤剂和自制自乳化制剂的变化情况相似。结果还表明,酚红因不被吸收,以它的浓度变化为参考来标定样品体积的变化是合理可行。
结论制剂粒径大小是影响药物吸收的关键,在某一粒径以上,粒径越小,药物吸收越快;在某一粒径以下,某些药物吸收可能与粒径大小无关。若剂型改进以后的制剂给药时的状态越能接近汤剂,则该改进效果越好,也越成功。本课题可为中药汤剂剂型改进提供新的方法和思路,有一定的意义。
Objective:Mahuang Tang(one of the famous recipe of traditional Chinese medicine) is as a research prescriotion,it contains Ephedra herb,ramulus cinnamomi,almond and liquiritia.Oil extracted from the herbs mix is as a oil phase,other extracted ingredients from the herbs mix are the drugs and excipient and these become self-emulsifying system by adding surfactant according to the definition of self-emulsifying drug delivery system(SEDDS).Adding water is to dissolve all the components and recover the status of decoction.Then compared the absorption of the Mahuang Tang and its self-emulsifying system in small intestine in situ,to study the similarities and differences of the absorbing between the two preparations.This study is a preliminary research,and the purpose is to improve the dosage form of Chinese medicinal formulations with new research methods and ideas.
Method:To extract fat-soluble components and water-soluble components of the ingredients,we applied extraction of the two-step approach,to prepare Mahuang Tang self-emulsifying system.Mark ingredients and particle size are for the analytical indicatrix.Combination of microscope and particle Size Analyzer we determined the particle size of Mahuang Tang,Mahuang Tang self-emulsifying system,Mahuang Tang-self-emulsifying system eliminated emulsifier and commercial formula after dissolved them in water.The absorption rate was investigated with perfusing small intestine of rats in situ.Fingerprints and the concentration of ephedrine and pseudoephedrine was determined using HPLC-electrochemical detection and the concentration of cinnamaldehyde was determined by RP-HPLC.
Results:The use of emulsifier is about 40 percent and combine use of lecithin and poloxamer(a ratio of 3:1)in the self-emusifying system.In this condition, emulsifying outcome is the best,the size of milk drops is smaller and similar to the size in Mahuang tang.They were(3.51±2.46)μm and(3.86±2.73)μm under microscope respectively.
The sensitivity and accuracy of detecting ephedrine and pseudoephedrine are good using reversed phase high-performance liquid chromatography(RP-HPLC) electrochemical detection,and also in quantitative determination of cinnamaldehyde using UV detection of the RP-HPLC.Samples are stable at room temperature.
The results of the preparation particle size and its absorption in the small intestine showed that the particle size of drug will affect its absorption,when the particle size is bigger than the size of a limited size,the absorption of ephedrine, pseudoephedrine and cinnamaldehyde will be affected.The absorbed amount of Ephedriae were decreased in the order of Mahuang tang,home-made self-emulsifying system and home-made self-emulsifying system eliminated emulsifier.These are consistent with their particle size.The absorbed amounts of Cinnamaldehyde is related to its concentration in the prparations and not related to the particle size,the higher the concentration the more absorptive the component.
The results of fingerprints show that peak height of licorice glycosides, ephedrine and pseudoephedrine after one hour administration were lower than their peak before administration,but the peak height after 1 hour and after 3 hour were similar.Excluding the volume change,the absorbed amount of Amygdalin was rare. The change was similar in the decoction and self-made self-emulsifying system.The results also showed that the phenol red was not absorbed,to use its concentration as reference to calibrate the change of solution volume is reasonable and feasible.
Conclusions:The particle size of preparations is the key point of affecting drug absorption in the limited size.The smaller the particle size,the faster the drug absorption;smaller than certain size,the absorption of some drugs may be no relation with particle size.If the preparations could be similar to its original decoction after the dosage form reforming,the work could be seem more successful.The results indicated that self-emulsifying drug delivery system is useful in the reforming of preparation decoction of traditional Chinese medicine.The method for improving dosage form of materials broth has a certain significance.
方法采用分两步提取的方法提取药材中的脂溶性成分和水溶性成分,以性状与粒径大小为考察指标,制备麻黄汤自乳化制剂;结合显微镜及粒度测定两种方法测定麻黄汤、麻黄汤自乳化制剂、麻黄汤未加乳化剂的制剂及市售单方颗粒水溶散后液体中微粒粒径;以大鼠在体肠循环的方法研究制剂的吸收情况,HPLC-电化学检测方法测定肠循环液中麻黄碱与伪麻黄碱的含量,RP-HPLC法测定桂皮醛含量,HPLC-电化学检测方法进行指纹图谱研究,比较麻黄汤、麻黄汤自乳化制剂、麻黄汤未加乳化剂的制剂及市售单方颗粒制得的麻黄汤在大鼠小肠的吸收情况。
结果药材提取结果:每克麻黄药材约得0.375克水提物:每克桂枝药材约得0.029克乙醚提取物及0.060克水提物;每克杏仁药材约得0.195克植物油及0.077克水提取物;每克甘草药材约得0.478克水提物。
自乳化制剂处方研究为:乳化剂的用量约为40%且泊洛沙姆和卵磷脂联合使用(比例为3∶1)时,乳化效果最好,显微镜下观察,产生的乳滴粒径较小,为(3.51±2.46)μm,与汤剂粒径(3.86±2.73)μm较为接近。
以电化学检测的反相HPLC定量测定麻黄碱和伪麻黄碱,检测灵敏度高,定量准确,是一个可行的方法;以紫外检测的反相HPLC定量测定桂皮醛,检测灵敏度高,定量准确,样品室温下稳定性好。
各制剂粒径大小及其大鼠在体肠吸收结果表明,药物粒径的大小可影响药物的吸收,当药物的粒径大于某一粒径时,就会对药物的吸收产生影响。吸收结果表明,汤剂中的麻黄碱和伪麻黄碱吸收率最大,其次为自制自乳化制剂,未加乳化剂的物理混合制剂相对最慢。这与其粒径大小相一致。桂皮醛的吸收以其含量最高的制剂中的吸收为最快最多,与粒径大小未表现出相关性,可能是由于其粒径还未超过对其吸收产生影响的粒径大小。
指纹图谱研究结果表明,甘草苷、麻黄碱及伪麻黄碱给药70分钟吸收量较多,但70分钟以后吸收量较小;苦杏仁苷给药前后峰高相当,若不计体积变化,其吸收很少。汤剂和自制自乳化制剂的变化情况相似。结果还表明,酚红因不被吸收,以它的浓度变化为参考来标定样品体积的变化是合理可行。
结论制剂粒径大小是影响药物吸收的关键,在某一粒径以上,粒径越小,药物吸收越快;在某一粒径以下,某些药物吸收可能与粒径大小无关。若剂型改进以后的制剂给药时的状态越能接近汤剂,则该改进效果越好,也越成功。本课题可为中药汤剂剂型改进提供新的方法和思路,有一定的意义。
Objective:Mahuang Tang(one of the famous recipe of traditional Chinese medicine) is as a research prescriotion,it contains Ephedra herb,ramulus cinnamomi,almond and liquiritia.Oil extracted from the herbs mix is as a oil phase,other extracted ingredients from the herbs mix are the drugs and excipient and these become self-emulsifying system by adding surfactant according to the definition of self-emulsifying drug delivery system(SEDDS).Adding water is to dissolve all the components and recover the status of decoction.Then compared the absorption of the Mahuang Tang and its self-emulsifying system in small intestine in situ,to study the similarities and differences of the absorbing between the two preparations.This study is a preliminary research,and the purpose is to improve the dosage form of Chinese medicinal formulations with new research methods and ideas.
Method:To extract fat-soluble components and water-soluble components of the ingredients,we applied extraction of the two-step approach,to prepare Mahuang Tang self-emulsifying system.Mark ingredients and particle size are for the analytical indicatrix.Combination of microscope and particle Size Analyzer we determined the particle size of Mahuang Tang,Mahuang Tang self-emulsifying system,Mahuang Tang-self-emulsifying system eliminated emulsifier and commercial formula after dissolved them in water.The absorption rate was investigated with perfusing small intestine of rats in situ.Fingerprints and the concentration of ephedrine and pseudoephedrine was determined using HPLC-electrochemical detection and the concentration of cinnamaldehyde was determined by RP-HPLC.
Results:The use of emulsifier is about 40 percent and combine use of lecithin and poloxamer(a ratio of 3:1)in the self-emusifying system.In this condition, emulsifying outcome is the best,the size of milk drops is smaller and similar to the size in Mahuang tang.They were(3.51±2.46)μm and(3.86±2.73)μm under microscope respectively.
The sensitivity and accuracy of detecting ephedrine and pseudoephedrine are good using reversed phase high-performance liquid chromatography(RP-HPLC) electrochemical detection,and also in quantitative determination of cinnamaldehyde using UV detection of the RP-HPLC.Samples are stable at room temperature.
The results of the preparation particle size and its absorption in the small intestine showed that the particle size of drug will affect its absorption,when the particle size is bigger than the size of a limited size,the absorption of ephedrine, pseudoephedrine and cinnamaldehyde will be affected.The absorbed amount of Ephedriae were decreased in the order of Mahuang tang,home-made self-emulsifying system and home-made self-emulsifying system eliminated emulsifier.These are consistent with their particle size.The absorbed amounts of Cinnamaldehyde is related to its concentration in the prparations and not related to the particle size,the higher the concentration the more absorptive the component.
The results of fingerprints show that peak height of licorice glycosides, ephedrine and pseudoephedrine after one hour administration were lower than their peak before administration,but the peak height after 1 hour and after 3 hour were similar.Excluding the volume change,the absorbed amount of Amygdalin was rare. The change was similar in the decoction and self-made self-emulsifying system.The results also showed that the phenol red was not absorbed,to use its concentration as reference to calibrate the change of solution volume is reasonable and feasible.
Conclusions:The particle size of preparations is the key point of affecting drug absorption in the limited size.The smaller the particle size,the faster the drug absorption;smaller than certain size,the absorption of some drugs may be no relation with particle size.If the preparations could be similar to its original decoction after the dosage form reforming,the work could be seem more successful.The results indicated that self-emulsifying drug delivery system is useful in the reforming of preparation decoction of traditional Chinese medicine.The method for improving dosage form of materials broth has a certain significance.
引文
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