无糖金钱草颗粒质量标准研究
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摘要
金钱草为报春花科珍珠菜属植物过路黄(Lysimachia christinae Hance)的干燥全草,是传统的清肝利胆药,或单方或组方,被广泛用于肝胆结石和泌尿系结石的治疗。金钱草的临床应用除了采用传统水煎剂外,还有多种金钱草单方制剂和以金钱草为主药的复方制剂在国内药品市场流通,其中以金钱草颗粒剂最为常见。传统的金钱草颗粒含有大量的糖,以满足制粒工艺和调节口味的需要。但随着糖尿病和肥胖症等疾病的发病率升高,大量患者期待无糖金钱草颗粒的问世。所以,重庆和平制药有限公司拟开发无糖金钱草颗粒,委托本课题组制定无糖金钱草颗粒的质量标准。
本文首先从原料药材金钱草中分离特有的化学成分作为对照品,从金钱草乙醇提取物的正丁醇萃取部分中分离得到3个黄酮类化合物,分别鉴定它们的结构为：槲皮素-3-O-α-L-鼠李糖基-(1→2)-β-D-半乳糖苷(1)、杨梅素-3,3’-二-O--α-L-鼠李糖苷(2)、槲皮素-3,3’-二-O-α-L-鼠李糖苷(3)。以槲皮素-3-O-α-L-鼠李糖基-(1→2)-β-D-半乳糖苷为对照品,建立了测定无糖金钱草颗粒中该化合物含量的高效液相色谱(HPLC)法；并对该方法进行了方法学评价。确定样品溶液制备方法为用30倍于样品量的甲醇,室温下超声提取样品30min,取15倍于样品量的续滤液减压蒸干,残留物用1倍于样品量的甲醇溶解。色谱条件为：phenomenex C18色谱柱(4.6 mm×150mm,5μm)；洗脱溶剂：乙腈-0.5%冰醋酸(A),0.5%冰醋酸水溶液(B)；洗脱程序：0～25 min,15%A；25～25.05 min,15%A→100%A；25.05～30 min,100%A;30～30.05 min,100%A→15%A；30.05～40 min 15%A；流速：1.0 mL·min-1；柱温：35℃；检测波长：255 nm。方法学考察证明,用该法测定无糖金钱草颗粒中槲皮素-3-O-α-L-鼠李糖基-(1→2)-β-D-半乳糖苷的含量,在0.2μg～20μg范围内线性关系良好,日内及日间精密度良好,对照品溶液和样品溶液在5天内稳定,加样回收率在95%左右。本文还建立了无糖金钱草颗粒总黄酮的含量测定方法。样品溶液制备方法为用10倍于样品量的甲醇,室温下超声提取30 min,过滤,取续滤液。以芦丁为对照品,用A1C13-甲醇溶液为显色剂,采用分光光度法,在410 nm测定样品溶液显色后的吸光度。对该方法进行方法学考察,证明该法在0.012 mg·mL-1～0.040 mg·mL-1范围内线性关系良好,日内及日间精密度良好,对照品溶液和样品溶液在4天内稳定,加样回收率为96.63%-97.59%,表明用该法测定无糖金钱草颗粒中总黄酮含量可行、可信。
本文建立了无糖金钱草颗粒的HPLC指纹图谱测定方法。确定样品溶液制备方法为用10倍于样品量的甲醇,超声提取30min后过滤,取3倍于样品量的续滤液,减压蒸干,残留物用1/5倍于样品量的甲醇溶解。优化了HPLC条件,使色谱图呈现尽量多的峰并使主要色谱峰基本达到基线分离,确定HPLC方法为选用phenomenex C18色谱柱(4.6 mm×150 mm,5μm),乙腈-0.5%冰醋酸(A)-0.5%冰醋酸水溶液(B)梯度洗脱,梯度程序：0～10 mmin,5%A；10～10.5 mmin,5%A→10%A；10.5～30 min 10%A→15%A；30～50 min 15%A→18%A；50～60min 18%A→20%A；60～60.5 mmin,20%A→100%A；60.5～70 min,100%A。流速1.0 mL·min-1,柱温30℃,检测波长255 nm。应用国家药典委员会2004年颁布的“中药色谱指纹图谱相似度评价系统A版”比较分析了6个无糖金钱草颗粒样品的指纹图谱,建立了无糖金钱草颗粒的标准指纹图谱,包括了19个色谱峰。
本文建立的无糖金钱草颗粒中槲皮素-3-O-α-L-鼠李糖基-(1→2)-p-D-半乳糖苷的HPLC含量测定法、总黄酮含量测定法、指纹图谱测定法均具有良好的重复性,且操作简单,可用于无糖金钱草颗粒的常规质量控制。
本文还对无糖金钱草颗粒进行了一般理化鉴别,测定了6批无糖金钱草颗粒样品的一系列指标,包括粒度、堆密度(包括松密度和紧密度)、干燥失重、水不溶物含量、炽灼残渣、重金属含量,证明了重庆和平制药有限公司试制的无糖金钱草颗粒符合国家药品食品监督管理局的要求。
Herba Lysimachiae, the dry whole plant of Lysimachia christinae Hance, is a common used traditional Chinese medicine, which has long been widely used as conservative treatment for hepatolithiasis. biliary calculus and urinary calculus. Besides used as decoction in traditional way, Herba Lysimachiae is prepared as preparations alone or together with other medicinal materials together, among which Jinqiancao Granules is the most common one. In traditional production process of Jinqiancao Granules, a lot of sugar is used to granulate and to correct the flavour. However, with the increasing incidence of diabetes and obesity, the Sugar-free Jinqiancao Granules is anticipated by a lot of patients. So, Chongqing Heping pharmaceutical Co., Ltd. is trying to develop Sugar-free Jinqiancao Granules and authorized us to establish quality standards for Sugar-free Jinqiancao Granules.
To prepare reference substances for quantifying ingredients of Herb Lysimachiae, the n-BuOH extraction of the material was studied on its chemical composition. Three flavonoids were isolated and their structures were identified as: quercetion-3-O-α-L-rhamnosyl-(1→2)-β-D-galactoside (1), myricetin-3,3'-di-O-a-L-rhamnoside (2), quercetion-3,3'-di-O-a-L-rhamnooside (3). Quercetion-3-O-α-L-rhamnosyl-(1→2)-β-D-galactoside was used as component marker to evaluate the quality of Sugar-free Jinqiancao Granules.
A quantitative method of quercetion-3-O-a-L-rhamnosyl-(1→2)-β-D-galactoside by HPLC was established and was methodologically validated. The preparation method of sample solution is determined as follows:Extract 1 g of sample by ultrasonic for 30 minutes with 30 mL of methanol at room temperature. Then,15 mL of subsequentfiltrate is evaporated to dryness and the residue is dissolved with 1 mL of methanol. The HPLC conditions were optimized as follows:phenomenex C18 column (4.6 mm×150 mm,5μm), acetonitrile-0.5% acetic acid (A) and H2O-0.5% acetic acid (B) as mobile phases and the gradient program was as follows:0-25 min,15% A; 25-25.05 min,15% A→100%A; 25.05-30 min,100%A; 30-30.05 min, 100%A→15%A; 30.05-40 min,15% A. The flow rate was 1.0 mL·min-1, the column temperature was 35℃and the detection wavelength was 255 nm. The methodological validation showed that the peak area was linearly correlated to the quantity of quercetion-3-O-α-L-rhamnosyl-(1→2)-β-D-galactoside within the range of 0.2μg-20μg, the sample solution was stable within 5 days, the intra-day and inter-day precision were good, and that the recovery of spiked analyte was around 95%.
The quantitative method of total flavonoids in Sugar-free Jinqiancao Granules was established too. Sample solution preparation method was determined as follows:Extract 2 g of sample by ultrasonic for 30 minutes with 20 mL of methanol at room temperature and take the subsequentfiltrate as sample solution. The quantity of total flavonoids in Sugar-free Jinqiancao Granules was determined with spectrometry with rutin as reference substance, with AlCl3-methanol solution as chromogenic reagent, and with O.D. measured at 410 nm. The methodological tests showed that there was a good linear correlation between O.D. and the concentration of flavonoids in the color reaction solution within the range of 0.012 mg·mL-1-0.040 mg·mL-1 of rutin, the intra-day and inter-day precision were good, the sample solution was stable within 4 days, and that the recovery of spiked analyte is 96.63%-97.59%. The quantitative method of total flavones in Sugar-free Jinqiancao Granules shows feasible and credible.
A method was established to assay the fingerprint of Sugar-free Jinqiancao Granules by HPLC. Sample solution should be prepared as follows:Extract 5 g of sample by ultrasonic for 30 minutes with 50 mL of methanol at room temperature,15 mL of subsequentfiltrate is evaporated and the residue is dissolved with 1 mL of methanol to give sample solution. The HPLC conditions were optimized as follows: phenomenex C18 column (4.6 mm×150 mm,5μm), acetonitrile-0.5% acetic acid (A) and H2O-0.5% acetic acid (B) as mobile phases and the gradient program was as follows:0-10 min,5% A; 10-10.5 min,5% A→10%A; 10.5-30 min,10%A→15%A; 30-50 min,15% A→18% A; 50-60 min,18% A→20%A; 60-60.5 min,20% A→100% A; 60.5-70 min,100% A. The flow rate was 1.0 mL·min-1, the column temperature was 30℃and the detection wavelength was 255 nm. Similarity evaluation system for chromatographic fingerprint of TCM (Edition A) issued by State Pharmcopoeia Committee was used to analyze the HPLC fingerprints of Sugar-free Jinqiancao Granules. The HPLC fingerprints of 6 batches of Sugar-free Jinqiancao Granules samples were compared and analyzed to give the standard HPLC fingerprint of Sugar-free Jinqiancao Granules which contains 19 common peaks.
The quantitative methods of quercetion-3-O-α-L-rhamnosyl-(1→-2)-β-D-galacto-side and total flavonoids in Sugar-free Jinqiancao Granules and the assay method of fingerprint of Sugar-free Jinqiancao Granules by HPLC were sensitive and accurate, easy to operate, and can be used for the routine quality control of Sugar-free Jinqiancao Granules.
A series of physical and chemical properties of Sugar-free Jinqiancao Granules were measured on six batches of Sugar-free Jinqiancao Granules samples, including granularity, bulk density and tapped density, weight loss on drying, content of water insoluble substance, residue of ignition, contents of heavy metals. The results showed that Sugar-free Jinqiancao Granules produced by Chongqing Heping pharmaceutical Co., Ltd was in line with SFDA's requirements.
本文首先从原料药材金钱草中分离特有的化学成分作为对照品,从金钱草乙醇提取物的正丁醇萃取部分中分离得到3个黄酮类化合物,分别鉴定它们的结构为：槲皮素-3-O-α-L-鼠李糖基-(1→2)-β-D-半乳糖苷(1)、杨梅素-3,3’-二-O--α-L-鼠李糖苷(2)、槲皮素-3,3’-二-O-α-L-鼠李糖苷(3)。以槲皮素-3-O-α-L-鼠李糖基-(1→2)-β-D-半乳糖苷为对照品,建立了测定无糖金钱草颗粒中该化合物含量的高效液相色谱(HPLC)法；并对该方法进行了方法学评价。确定样品溶液制备方法为用30倍于样品量的甲醇,室温下超声提取样品30min,取15倍于样品量的续滤液减压蒸干,残留物用1倍于样品量的甲醇溶解。色谱条件为：phenomenex C18色谱柱(4.6 mm×150mm,5μm)；洗脱溶剂：乙腈-0.5%冰醋酸(A),0.5%冰醋酸水溶液(B)；洗脱程序：0～25 min,15%A；25～25.05 min,15%A→100%A；25.05～30 min,100%A;30～30.05 min,100%A→15%A；30.05～40 min 15%A；流速：1.0 mL·min-1；柱温：35℃；检测波长：255 nm。方法学考察证明,用该法测定无糖金钱草颗粒中槲皮素-3-O-α-L-鼠李糖基-(1→2)-β-D-半乳糖苷的含量,在0.2μg～20μg范围内线性关系良好,日内及日间精密度良好,对照品溶液和样品溶液在5天内稳定,加样回收率在95%左右。本文还建立了无糖金钱草颗粒总黄酮的含量测定方法。样品溶液制备方法为用10倍于样品量的甲醇,室温下超声提取30 min,过滤,取续滤液。以芦丁为对照品,用A1C13-甲醇溶液为显色剂,采用分光光度法,在410 nm测定样品溶液显色后的吸光度。对该方法进行方法学考察,证明该法在0.012 mg·mL-1～0.040 mg·mL-1范围内线性关系良好,日内及日间精密度良好,对照品溶液和样品溶液在4天内稳定,加样回收率为96.63%-97.59%,表明用该法测定无糖金钱草颗粒中总黄酮含量可行、可信。
本文建立了无糖金钱草颗粒的HPLC指纹图谱测定方法。确定样品溶液制备方法为用10倍于样品量的甲醇,超声提取30min后过滤,取3倍于样品量的续滤液,减压蒸干,残留物用1/5倍于样品量的甲醇溶解。优化了HPLC条件,使色谱图呈现尽量多的峰并使主要色谱峰基本达到基线分离,确定HPLC方法为选用phenomenex C18色谱柱(4.6 mm×150 mm,5μm),乙腈-0.5%冰醋酸(A)-0.5%冰醋酸水溶液(B)梯度洗脱,梯度程序：0～10 mmin,5%A；10～10.5 mmin,5%A→10%A；10.5～30 min 10%A→15%A；30～50 min 15%A→18%A；50～60min 18%A→20%A；60～60.5 mmin,20%A→100%A；60.5～70 min,100%A。流速1.0 mL·min-1,柱温30℃,检测波长255 nm。应用国家药典委员会2004年颁布的“中药色谱指纹图谱相似度评价系统A版”比较分析了6个无糖金钱草颗粒样品的指纹图谱,建立了无糖金钱草颗粒的标准指纹图谱,包括了19个色谱峰。
本文建立的无糖金钱草颗粒中槲皮素-3-O-α-L-鼠李糖基-(1→2)-p-D-半乳糖苷的HPLC含量测定法、总黄酮含量测定法、指纹图谱测定法均具有良好的重复性,且操作简单,可用于无糖金钱草颗粒的常规质量控制。
本文还对无糖金钱草颗粒进行了一般理化鉴别,测定了6批无糖金钱草颗粒样品的一系列指标,包括粒度、堆密度(包括松密度和紧密度)、干燥失重、水不溶物含量、炽灼残渣、重金属含量,证明了重庆和平制药有限公司试制的无糖金钱草颗粒符合国家药品食品监督管理局的要求。
Herba Lysimachiae, the dry whole plant of Lysimachia christinae Hance, is a common used traditional Chinese medicine, which has long been widely used as conservative treatment for hepatolithiasis. biliary calculus and urinary calculus. Besides used as decoction in traditional way, Herba Lysimachiae is prepared as preparations alone or together with other medicinal materials together, among which Jinqiancao Granules is the most common one. In traditional production process of Jinqiancao Granules, a lot of sugar is used to granulate and to correct the flavour. However, with the increasing incidence of diabetes and obesity, the Sugar-free Jinqiancao Granules is anticipated by a lot of patients. So, Chongqing Heping pharmaceutical Co., Ltd. is trying to develop Sugar-free Jinqiancao Granules and authorized us to establish quality standards for Sugar-free Jinqiancao Granules.
To prepare reference substances for quantifying ingredients of Herb Lysimachiae, the n-BuOH extraction of the material was studied on its chemical composition. Three flavonoids were isolated and their structures were identified as: quercetion-3-O-α-L-rhamnosyl-(1→2)-β-D-galactoside (1), myricetin-3,3'-di-O-a-L-rhamnoside (2), quercetion-3,3'-di-O-a-L-rhamnooside (3). Quercetion-3-O-α-L-rhamnosyl-(1→2)-β-D-galactoside was used as component marker to evaluate the quality of Sugar-free Jinqiancao Granules.
A quantitative method of quercetion-3-O-a-L-rhamnosyl-(1→2)-β-D-galactoside by HPLC was established and was methodologically validated. The preparation method of sample solution is determined as follows:Extract 1 g of sample by ultrasonic for 30 minutes with 30 mL of methanol at room temperature. Then,15 mL of subsequentfiltrate is evaporated to dryness and the residue is dissolved with 1 mL of methanol. The HPLC conditions were optimized as follows:phenomenex C18 column (4.6 mm×150 mm,5μm), acetonitrile-0.5% acetic acid (A) and H2O-0.5% acetic acid (B) as mobile phases and the gradient program was as follows:0-25 min,15% A; 25-25.05 min,15% A→100%A; 25.05-30 min,100%A; 30-30.05 min, 100%A→15%A; 30.05-40 min,15% A. The flow rate was 1.0 mL·min-1, the column temperature was 35℃and the detection wavelength was 255 nm. The methodological validation showed that the peak area was linearly correlated to the quantity of quercetion-3-O-α-L-rhamnosyl-(1→2)-β-D-galactoside within the range of 0.2μg-20μg, the sample solution was stable within 5 days, the intra-day and inter-day precision were good, and that the recovery of spiked analyte was around 95%.
The quantitative method of total flavonoids in Sugar-free Jinqiancao Granules was established too. Sample solution preparation method was determined as follows:Extract 2 g of sample by ultrasonic for 30 minutes with 20 mL of methanol at room temperature and take the subsequentfiltrate as sample solution. The quantity of total flavonoids in Sugar-free Jinqiancao Granules was determined with spectrometry with rutin as reference substance, with AlCl3-methanol solution as chromogenic reagent, and with O.D. measured at 410 nm. The methodological tests showed that there was a good linear correlation between O.D. and the concentration of flavonoids in the color reaction solution within the range of 0.012 mg·mL-1-0.040 mg·mL-1 of rutin, the intra-day and inter-day precision were good, the sample solution was stable within 4 days, and that the recovery of spiked analyte is 96.63%-97.59%. The quantitative method of total flavones in Sugar-free Jinqiancao Granules shows feasible and credible.
A method was established to assay the fingerprint of Sugar-free Jinqiancao Granules by HPLC. Sample solution should be prepared as follows:Extract 5 g of sample by ultrasonic for 30 minutes with 50 mL of methanol at room temperature,15 mL of subsequentfiltrate is evaporated and the residue is dissolved with 1 mL of methanol to give sample solution. The HPLC conditions were optimized as follows: phenomenex C18 column (4.6 mm×150 mm,5μm), acetonitrile-0.5% acetic acid (A) and H2O-0.5% acetic acid (B) as mobile phases and the gradient program was as follows:0-10 min,5% A; 10-10.5 min,5% A→10%A; 10.5-30 min,10%A→15%A; 30-50 min,15% A→18% A; 50-60 min,18% A→20%A; 60-60.5 min,20% A→100% A; 60.5-70 min,100% A. The flow rate was 1.0 mL·min-1, the column temperature was 30℃and the detection wavelength was 255 nm. Similarity evaluation system for chromatographic fingerprint of TCM (Edition A) issued by State Pharmcopoeia Committee was used to analyze the HPLC fingerprints of Sugar-free Jinqiancao Granules. The HPLC fingerprints of 6 batches of Sugar-free Jinqiancao Granules samples were compared and analyzed to give the standard HPLC fingerprint of Sugar-free Jinqiancao Granules which contains 19 common peaks.
The quantitative methods of quercetion-3-O-α-L-rhamnosyl-(1→-2)-β-D-galacto-side and total flavonoids in Sugar-free Jinqiancao Granules and the assay method of fingerprint of Sugar-free Jinqiancao Granules by HPLC were sensitive and accurate, easy to operate, and can be used for the routine quality control of Sugar-free Jinqiancao Granules.
A series of physical and chemical properties of Sugar-free Jinqiancao Granules were measured on six batches of Sugar-free Jinqiancao Granules samples, including granularity, bulk density and tapped density, weight loss on drying, content of water insoluble substance, residue of ignition, contents of heavy metals. The results showed that Sugar-free Jinqiancao Granules produced by Chongqing Heping pharmaceutical Co., Ltd was in line with SFDA's requirements.
引文
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[37]王学,沈文律,黄孝伦等.金钱草抗移植排斥作用的实验研究[J].华西医科大学学报,1996,27(2)：224.
[38]林启云,谢金鲜,黄世英等.金钱草冲剂的药理实验[J].广西中医药,1990, 13(6)：40-41.
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[40]孟宪萌,于年海.三金利胆排石汤治疗胆石症76例[J].辽宁中医药大学学报,2009,11(2)：123-124.
[41]金庆江.攻积排石汤治疗胆石症195例体会[J].云南中医学院学报,2003,26(2)：34-35.
[42]刘强.40例自拟金钱茵陈汤治疗胆囊炎观察[J].中国实用医药,2007,2(22)：66-67.
[43]唐远山,冯琳,段海楠等.金郁小柴胡汤治疗慢性胆囊炎45例[J].陕西中医,2008,29(4)：462-463.
[44]李本觉,贺文容.排石汤治疗尿路结石1123例[J].新中医,2009,41(10)：73.
[45]梅志高.利尿排石汤治疗肾输尿管结石100例[J].实用中西医结合临床,2008,8(5)：24.
[46]叶艳军,腾淑玲,吴志民.体外碎石后服用中药排石汤治疗肾结石43例[J].中医杂志,2009,50(2)：178.
[47]李炳照.单味金钱草为主综合治疗婴儿肝炎综合征41例临床观察[J].临床儿科杂志,1987,5(5)：300-301.
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[52]赵志勇,郭在培.金钱草引起面部接触性皮炎9例[J].临床皮肤科杂志,2003,32(4)：198.
[53]戈升荣,安富荣,袁静等.排石合剂质量标准研究[J].中草药,2000,31(12)：904-906.
[54]沈德凤,焦艳.金钱草颗粒剂质量标准的研究[J].中国现代应用药学杂志,2009,26(8)：673-674.
[55]雷灼雨.反相高效液相色谱法测定金钱草颗粒的含量[J].药物鉴定,2007,16(16)：438.
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