左金滴丸有效部位及制剂工艺研究
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摘要
左金丸出自朱丹溪《丹溪心法火六》,是我国治疗脾胃病的经典名方,原方由黄连六两和吴茱萸一两组成,共为末,做成水丸或蒸饼为丸,白汤服下。功效能清泻肝火,降逆止呕。用于治疗肝经火旺之胁肋胀痛,呕吐吞酸,嘈杂嗳气,口苦咽干,舌红,脉弦数。目前主要用于消化系统疾病,尤其是胃炎、溃疡等症。近年来,药理研究表明左金丸中的有效成分主要是黄连中的生物碱类成分,吴茱萸中的生物碱类及苦味素类成分。由于消化系统疾病在临床上十分常见,现已成为严重危害我国人民身心健康的重大疾病。因此研发针对性强、疗效确切的中医名方有巨大的市场价值。
因此,本论文对左金丸中黄连、吴茱萸分别进行了有效部位研究,及相应的质量标准研究,并进行了左金丸有效部位滴丸的制剂成型工艺及质量标准研究,共分为九章。
第一章对左金丸中黄连、吴茱萸的化学成分及药理研究,左金丸的药理研究及临床应用分别加以综述。并对中药滴丸的研究进展、特点及新辅料、新技术、新设备在中药滴丸中的应用进行了总结,共引用文献116篇。
第二章对吴茱萸的有效部位进行了化学成分研究,吴茱萸分离得到了7个化学成分,鉴定了其中6个化合物,其中有四个为生物碱类化合物,分别为:吴茱萸碱(Evodiamine),吴茱萸次碱(Rutaecarpine),雷特西宁(rhetsinine)及吴茱萸喹酮碱(Evocarpine);还有苦味素类成分吴茱萸内酯(Limonin);另一个为-谷甾醇( -sitosterol)。
第三章黄连有效部位的制备工艺研究。
首先优选了黄连有效部位的提取工艺。以总生物碱的转移率为检测指标,对黄连的提取工艺进行了考察,经数据分析,得出最佳提取工艺为:A2乙醇,B3倍量,提取D3次,每次C2小时。
其次考察了黄连有效部位的纯化富集工艺。最终确定用E3倍水F2℃提取G2min,再用盐酸调pH值H1,并将提取液冷藏I2h后,滤过,滤渣为有效部位Ⅰ;滤液通过强酸性阳离子交换树脂,交换后,用水冲洗柱体洗去水溶性杂质,再将吸附有总生物碱的树脂在空气中晾干(放置一夜即可),加K3倍氨水浸泡J3h,再将碱化的树脂用M2%乙醇提取3次,每次N2h,合并提取液并干燥至干即得有效部位Ⅱ。有效部位Ⅰ、Ⅱ混合即得黄连有效部位。
第四章吴茱萸有效部位的制备工艺研究。
首先优选了吴茱萸有效部位的提取工艺。以吴茱萸次碱的转移率为检测指标,对吴茱萸的提取工艺进行了考察,经数据分析,得出最佳提取工艺为:A3乙醇,B3倍量,提取D2次,每次C2小时。
其次考察了吴茱萸有效部位的纯化富集工艺。最终确定吴茱萸乙醇提取物用10倍量水分散,用10%NaOH溶液调pH10～11后,再用10倍量乙酸乙酯萃取两次,萃取液合并,浓缩,干燥即得。
第五章黄连有效部位的质量标准研究
1采用紫外法测定黄连有效部位中总生物碱的含量。以盐酸小檗碱为对照品,检测波长350nm,所得线性方程为:y=66.634x+0.0432,r=0.9992(n=7)。表明盐酸小檗碱在350nm检测波长下,浓度在0.00216～0.00864mg/ml之间与吸光度成良好线性关系。有效部位中总生物碱含量为70%左右,加样回收率为101.97%,RSD=1.205%。(n=5)。
2采用高效液相法对有效部位中盐酸小檗碱、盐酸巴马汀进行了含量测定。盐酸小檗碱标准曲线为y=3317.6x+42.854,r=0.9997(n=5),表明盐酸小檗碱在0.204～2.04ug范围内质量与峰面积成线性关系。经测定有效部位中盐酸小檗碱含量为31%,加样回收率为102.44%,RSD=1.37%(n=5)。盐酸巴马汀标准曲线为y=3311.4x+45.634,r=0.9996(n=6),表明盐酸巴马汀在0.100～2.000ug范围内质量与峰面积成线性关系。经测定有效部位中盐酸巴马汀含量为5%,加样回收率为98.02%,RSD%=1.95%(n=5)。有效部位中所测两种生物碱总含量为36%左右,并且通过测定检测波长下两种对照品的响应值确定了仅以盐酸小檗碱为对照测定两种生物碱的计算公式,方便了测定。
第六章吴茱萸有效部位的质量标准研究
采用高效液相法对有效部位中吴茱萸碱、吴茱萸次碱和吴茱萸内酯进行了含量测定。吴茱萸碱标准曲线y=8800.5x+17.524,r=0.9999(n=5),表明吴茱萸碱在0.0892～0.8920ug范围内质量与峰面积成良好线性关系。经测定有效部位中吴茱萸碱含量为4.10%,加样回收率为102.50%,RSD%=1.76%(n=5)。吴茱萸次碱标准曲线为y=3311.4x+45.634,r=0.9999(n=5),表明吴茱萸次碱在0.100～2.000ug范围内质量与峰面积成线性关系。经测定有效部位中吴茱萸次碱含量为2.40%,加样回收率为100.85%,RSD%=1.64%(n=5)。吴茱萸内酯标准曲线y=157.65x+8.56,r=0.9999(n=5),表明吴茱萸内酯在2.810～8.430ug范围内质量与峰面积成线性关系。经测定有效部位中吴茱萸内酯含量为35.70%,加样回收率为98.81%,RSD%=1.29%(n=5)。有效部位中所测三种有效成分总含量为40%左右,并且通过测定检测波长下三种对照品的响应值确定了仅以吴茱萸次碱为对照测定三种有效成分的计算公式,方便了测定。
第七章黄连、吴茱萸有效部位的指纹图谱的建立
用HPLC法分别建立了黄连有效部位、吴茱萸有效部位的指纹图谱,并通过分别考察五批有效部位指纹图谱,建立了有效部位的对照指纹图谱。
第八章左金丸有效部位的滴丸制剂成型工艺及质量标准研究。考察了滴丸制剂成型工艺,确定了基质种类以及基质与有效部位的混合比例。并建立了滴丸的定性与定量的质量标准。
第九章总结与讨论
Zuojin Wan is a classical and efficient formula specified for digestive systemdisease. It was presented in DAN XI XIN FA, simply composed of RhizomaCoptidis 18g and Fructus Evodiae 3g. The medicinal materials should be pound orground into powder, then make water-paste pill, and taken with rice-water. It hasthe effects of clearing away liver-fire, and descending rebellious qi .Using forliver-fire due to depression of liver-qi with hypochondriac distention and pain,bitterness and dryness in the mouth, and incoordination between the liver andstomach with acid regurgitation and vomiting. It is Red tongue, wiry andfrequent pulse. Zuojin Wan is mainly used for disease of digestive system,especially for gastritis and peptic ulcers. For the past few years, pharmacologyresearch indicated that the effective component of Zuojin Wan is the alkaloids inRhizoma Coptidis, the alkaloids in Fructus Evodiae, and the bitter principles inFructus Evodiae. For the disease of digestive system is very common in clinic, ithas become the most harmful disease for the people. As the result, to research thetraditional Chinese formula with exactitude direction, effective therapy havinglarge market value.
Therefore, in my thesis, I have separately researched the effective component inRhizoma Coptidis and Fructus Evodiae. Then observe the quality specification, aswell as the preparing technology of Zuojin Wan effective fraction dripping pillsand the quality specification. This dissertation has nine parts.
Chapter 1 In this chapter, first separately made an overview of thechemical composition of Rhizoma Coptidis, Fructus Evodiae and Zuojin Wan, aswell as its pharmacology and clinical research. Then, the new development,adjuvant, technique, equipment about dropping pill made of Chinese herbs weresummed up and analyzed. 116 references were cited.
Chapter 2 the effective fraction was researched in this part. Sevencompounds were isolated from the Fructus Evodiae. Six of them were evaluated,and four were Alkaloids. They are Evodiamine , Rutaecarpine,Rhetsinine,Evocarpine, Limonin, and ?-sitosterol.
Chapter 3 optimized the technology of preparing of Rhizoma Coptidis’seffective fraction. The first part is to optimize the technology of extractingeffective fraction of Rhizoma Coptidis. The optimum technology of extraction wasstudied by orthogonal test using the content of Alkaloids as selecting index. The factors of the orthogonal test table L9 (34) were alcohol concentration (A), alcoholquantity (B), extracting time(C), and extracting times (D). As a result, theoptimum parameters were A2B3C2D3.
The second part is to optimizing the technology of purifying and enrichingRhizoma Coptidis’s effective fraction. The factors of the orthogonal test table L9(34) were water quantity (E), temperature (F), extracting time (G), and PH (H). Asa result, the optimum parameters were E3F2G2H1. Cold-storage the extract for (I2)hours, filter it, and the filter residue was the effective fraction ?.? Then the filterliquor goes through the cation exchange resin. After adsorption, using water flushaway water-solubility foreign substance. To open-air dry the cation exchange resinfor one night. Add ammonia (K3), keep 3 hour. After that, to extract the cationexchange resin, using alcohol (M2%) for 3 times. Each one was last for (N2) hour.To get all extract together, dry them. That is the effective fractionⅡ. Mix the partⅠandⅡ,that is the effective fraction of Rhizoma Coptidis.
Chapter 4 optimized the technology of preparing of Fructus Evodiae’seffective fraction. The first part is to optimize the technology of extractingeffective fraction of Fructus Evodiae. The optimum technology of extraction wasstudied by orthogonal test using the content of Rutaecarpine as selecting index.The factors of the orthogonal test table L9 (34) were alcohol concentration (A),alcohol quantity (B), extracting time(C), and extracting times (D). As a result, theoptimum parameters were A3B3C2D2.
The second part is to optimizing the technology of purifying and enrichingFructus Evodiae effective fraction. Finally, I optimized the technology. It is usingalcohol extract, ten times water dilute, add 10% NaOH (to Ph=10-11). Etac (tentimes) extract 3 times. To get all extract together, dry them. That is the effectivefraction of Fructus Evodiae.
Chapter 5 establishes methods of determining the effective fraction ofRhizoma Coptidis.
Firstly, using Berberine as reference substance we determined the content oftotal alkaloid with UV method (350nm). The calibration curve(y=66.634x+0.0432)is linear at ranges of 0.00216～0.0864mg/ml(r=9992). And the content was 70 %,the average recoveries were 101.97 %( RSD=1.205%, n=5).
Secondly, the contents of index compounds including Berberine, Palmatine aredetermined by HPLC. The calibration curves(y=3317.6x+42.854) are linear atranges of 0.204～2.04ug(for Berberine, r=0.9997). And the content was 31%, theaverage recoveries were 102.44 %( RSD=1.37%, n=5). The calibrationcurves(y=3311.4x+45.634) are linear at ranges of 0.0732ug～0.732ug(forPalmatine, r=0.9996), The content was 5 %, the average recoveries were 98.02%(RSD=1.95%,n=5). So the content of two alkaloids was 36%, consideringthe response value. It is convenience for us to analyze it, only using Berberine asreference substance.
Chapter 6 establishes methods of determining Evodiamine, Rutaecarpine, andLimonin of the effective fraction of Fructus Evodiae.
The contents of index compounds including Evodiamine, Rutaecarpine Limoninare determined by HPLC. The calibration curves(y=8800.5x+17.524) are linear atranges of 0.0892～0.8920ug(for Evodiamine, r=0.9999). And the content was4.10%, the average recoveries were 102.50 %( RSD=1.76%, n=5). The calibrationcurves(y=3311.4x+45.634) are linear at ranges of 0.100ug～2.000ug(forRutaecarpine, r=0.9999), The content was 2.4%, the average recoveries were100.85%(RSD=1.64%,n=5). The calibration curves(y=157.65x+8.56) are linear atranges of 2.810ug～8.430ug(for Limonin, r=0.9999), The content was 35.70%, theaverage recoveries were 98.81%(RSD=1.29%,n=5). So the content of threealkaloids was 40%, considering the response value. It is convenience for us toanalyze it, only using Rutaecarpine as reference substance.
Chapter 7 In this part we established HPLC fingerprint of the effectivefraction of Rhizoma Coptidis and Fructus Evodiae. So we can accurately controlthe overall quality of effective fraction with fingerprint.
Chapter 8 In this part, we researched on preparation technology ofdropping pills made of effective fraction of Zuojin Wan. And we established thequality standard of the dropping pill using the method of HPLC.
Chapter 9 analysis and summary
因此,本论文对左金丸中黄连、吴茱萸分别进行了有效部位研究,及相应的质量标准研究,并进行了左金丸有效部位滴丸的制剂成型工艺及质量标准研究,共分为九章。
第一章对左金丸中黄连、吴茱萸的化学成分及药理研究,左金丸的药理研究及临床应用分别加以综述。并对中药滴丸的研究进展、特点及新辅料、新技术、新设备在中药滴丸中的应用进行了总结,共引用文献116篇。
第二章对吴茱萸的有效部位进行了化学成分研究,吴茱萸分离得到了7个化学成分,鉴定了其中6个化合物,其中有四个为生物碱类化合物,分别为:吴茱萸碱(Evodiamine),吴茱萸次碱(Rutaecarpine),雷特西宁(rhetsinine)及吴茱萸喹酮碱(Evocarpine);还有苦味素类成分吴茱萸内酯(Limonin);另一个为-谷甾醇( -sitosterol)。
第三章黄连有效部位的制备工艺研究。
首先优选了黄连有效部位的提取工艺。以总生物碱的转移率为检测指标,对黄连的提取工艺进行了考察,经数据分析,得出最佳提取工艺为:A2乙醇,B3倍量,提取D3次,每次C2小时。
其次考察了黄连有效部位的纯化富集工艺。最终确定用E3倍水F2℃提取G2min,再用盐酸调pH值H1,并将提取液冷藏I2h后,滤过,滤渣为有效部位Ⅰ;滤液通过强酸性阳离子交换树脂,交换后,用水冲洗柱体洗去水溶性杂质,再将吸附有总生物碱的树脂在空气中晾干(放置一夜即可),加K3倍氨水浸泡J3h,再将碱化的树脂用M2%乙醇提取3次,每次N2h,合并提取液并干燥至干即得有效部位Ⅱ。有效部位Ⅰ、Ⅱ混合即得黄连有效部位。
第四章吴茱萸有效部位的制备工艺研究。
首先优选了吴茱萸有效部位的提取工艺。以吴茱萸次碱的转移率为检测指标,对吴茱萸的提取工艺进行了考察,经数据分析,得出最佳提取工艺为:A3乙醇,B3倍量,提取D2次,每次C2小时。
其次考察了吴茱萸有效部位的纯化富集工艺。最终确定吴茱萸乙醇提取物用10倍量水分散,用10%NaOH溶液调pH10～11后,再用10倍量乙酸乙酯萃取两次,萃取液合并,浓缩,干燥即得。
第五章黄连有效部位的质量标准研究
1采用紫外法测定黄连有效部位中总生物碱的含量。以盐酸小檗碱为对照品,检测波长350nm,所得线性方程为:y=66.634x+0.0432,r=0.9992(n=7)。表明盐酸小檗碱在350nm检测波长下,浓度在0.00216～0.00864mg/ml之间与吸光度成良好线性关系。有效部位中总生物碱含量为70%左右,加样回收率为101.97%,RSD=1.205%。(n=5)。
2采用高效液相法对有效部位中盐酸小檗碱、盐酸巴马汀进行了含量测定。盐酸小檗碱标准曲线为y=3317.6x+42.854,r=0.9997(n=5),表明盐酸小檗碱在0.204～2.04ug范围内质量与峰面积成线性关系。经测定有效部位中盐酸小檗碱含量为31%,加样回收率为102.44%,RSD=1.37%(n=5)。盐酸巴马汀标准曲线为y=3311.4x+45.634,r=0.9996(n=6),表明盐酸巴马汀在0.100～2.000ug范围内质量与峰面积成线性关系。经测定有效部位中盐酸巴马汀含量为5%,加样回收率为98.02%,RSD%=1.95%(n=5)。有效部位中所测两种生物碱总含量为36%左右,并且通过测定检测波长下两种对照品的响应值确定了仅以盐酸小檗碱为对照测定两种生物碱的计算公式,方便了测定。
第六章吴茱萸有效部位的质量标准研究
采用高效液相法对有效部位中吴茱萸碱、吴茱萸次碱和吴茱萸内酯进行了含量测定。吴茱萸碱标准曲线y=8800.5x+17.524,r=0.9999(n=5),表明吴茱萸碱在0.0892～0.8920ug范围内质量与峰面积成良好线性关系。经测定有效部位中吴茱萸碱含量为4.10%,加样回收率为102.50%,RSD%=1.76%(n=5)。吴茱萸次碱标准曲线为y=3311.4x+45.634,r=0.9999(n=5),表明吴茱萸次碱在0.100～2.000ug范围内质量与峰面积成线性关系。经测定有效部位中吴茱萸次碱含量为2.40%,加样回收率为100.85%,RSD%=1.64%(n=5)。吴茱萸内酯标准曲线y=157.65x+8.56,r=0.9999(n=5),表明吴茱萸内酯在2.810～8.430ug范围内质量与峰面积成线性关系。经测定有效部位中吴茱萸内酯含量为35.70%,加样回收率为98.81%,RSD%=1.29%(n=5)。有效部位中所测三种有效成分总含量为40%左右,并且通过测定检测波长下三种对照品的响应值确定了仅以吴茱萸次碱为对照测定三种有效成分的计算公式,方便了测定。
第七章黄连、吴茱萸有效部位的指纹图谱的建立
用HPLC法分别建立了黄连有效部位、吴茱萸有效部位的指纹图谱,并通过分别考察五批有效部位指纹图谱,建立了有效部位的对照指纹图谱。
第八章左金丸有效部位的滴丸制剂成型工艺及质量标准研究。考察了滴丸制剂成型工艺,确定了基质种类以及基质与有效部位的混合比例。并建立了滴丸的定性与定量的质量标准。
第九章总结与讨论
Zuojin Wan is a classical and efficient formula specified for digestive systemdisease. It was presented in DAN XI XIN FA, simply composed of RhizomaCoptidis 18g and Fructus Evodiae 3g. The medicinal materials should be pound orground into powder, then make water-paste pill, and taken with rice-water. It hasthe effects of clearing away liver-fire, and descending rebellious qi .Using forliver-fire due to depression of liver-qi with hypochondriac distention and pain,bitterness and dryness in the mouth, and incoordination between the liver andstomach with acid regurgitation and vomiting. It is Red tongue, wiry andfrequent pulse. Zuojin Wan is mainly used for disease of digestive system,especially for gastritis and peptic ulcers. For the past few years, pharmacologyresearch indicated that the effective component of Zuojin Wan is the alkaloids inRhizoma Coptidis, the alkaloids in Fructus Evodiae, and the bitter principles inFructus Evodiae. For the disease of digestive system is very common in clinic, ithas become the most harmful disease for the people. As the result, to research thetraditional Chinese formula with exactitude direction, effective therapy havinglarge market value.
Therefore, in my thesis, I have separately researched the effective component inRhizoma Coptidis and Fructus Evodiae. Then observe the quality specification, aswell as the preparing technology of Zuojin Wan effective fraction dripping pillsand the quality specification. This dissertation has nine parts.
Chapter 1 In this chapter, first separately made an overview of thechemical composition of Rhizoma Coptidis, Fructus Evodiae and Zuojin Wan, aswell as its pharmacology and clinical research. Then, the new development,adjuvant, technique, equipment about dropping pill made of Chinese herbs weresummed up and analyzed. 116 references were cited.
Chapter 2 the effective fraction was researched in this part. Sevencompounds were isolated from the Fructus Evodiae. Six of them were evaluated,and four were Alkaloids. They are Evodiamine , Rutaecarpine,Rhetsinine,Evocarpine, Limonin, and ?-sitosterol.
Chapter 3 optimized the technology of preparing of Rhizoma Coptidis’seffective fraction. The first part is to optimize the technology of extractingeffective fraction of Rhizoma Coptidis. The optimum technology of extraction wasstudied by orthogonal test using the content of Alkaloids as selecting index. The factors of the orthogonal test table L9 (34) were alcohol concentration (A), alcoholquantity (B), extracting time(C), and extracting times (D). As a result, theoptimum parameters were A2B3C2D3.
The second part is to optimizing the technology of purifying and enrichingRhizoma Coptidis’s effective fraction. The factors of the orthogonal test table L9(34) were water quantity (E), temperature (F), extracting time (G), and PH (H). Asa result, the optimum parameters were E3F2G2H1. Cold-storage the extract for (I2)hours, filter it, and the filter residue was the effective fraction ?.? Then the filterliquor goes through the cation exchange resin. After adsorption, using water flushaway water-solubility foreign substance. To open-air dry the cation exchange resinfor one night. Add ammonia (K3), keep 3 hour. After that, to extract the cationexchange resin, using alcohol (M2%) for 3 times. Each one was last for (N2) hour.To get all extract together, dry them. That is the effective fractionⅡ. Mix the partⅠandⅡ,that is the effective fraction of Rhizoma Coptidis.
Chapter 4 optimized the technology of preparing of Fructus Evodiae’seffective fraction. The first part is to optimize the technology of extractingeffective fraction of Fructus Evodiae. The optimum technology of extraction wasstudied by orthogonal test using the content of Rutaecarpine as selecting index.The factors of the orthogonal test table L9 (34) were alcohol concentration (A),alcohol quantity (B), extracting time(C), and extracting times (D). As a result, theoptimum parameters were A3B3C2D2.
The second part is to optimizing the technology of purifying and enrichingFructus Evodiae effective fraction. Finally, I optimized the technology. It is usingalcohol extract, ten times water dilute, add 10% NaOH (to Ph=10-11). Etac (tentimes) extract 3 times. To get all extract together, dry them. That is the effectivefraction of Fructus Evodiae.
Chapter 5 establishes methods of determining the effective fraction ofRhizoma Coptidis.
Firstly, using Berberine as reference substance we determined the content oftotal alkaloid with UV method (350nm). The calibration curve(y=66.634x+0.0432)is linear at ranges of 0.00216～0.0864mg/ml(r=9992). And the content was 70 %,the average recoveries were 101.97 %( RSD=1.205%, n=5).
Secondly, the contents of index compounds including Berberine, Palmatine aredetermined by HPLC. The calibration curves(y=3317.6x+42.854) are linear atranges of 0.204～2.04ug(for Berberine, r=0.9997). And the content was 31%, theaverage recoveries were 102.44 %( RSD=1.37%, n=5). The calibrationcurves(y=3311.4x+45.634) are linear at ranges of 0.0732ug～0.732ug(forPalmatine, r=0.9996), The content was 5 %, the average recoveries were 98.02%(RSD=1.95%,n=5). So the content of two alkaloids was 36%, consideringthe response value. It is convenience for us to analyze it, only using Berberine asreference substance.
Chapter 6 establishes methods of determining Evodiamine, Rutaecarpine, andLimonin of the effective fraction of Fructus Evodiae.
The contents of index compounds including Evodiamine, Rutaecarpine Limoninare determined by HPLC. The calibration curves(y=8800.5x+17.524) are linear atranges of 0.0892～0.8920ug(for Evodiamine, r=0.9999). And the content was4.10%, the average recoveries were 102.50 %( RSD=1.76%, n=5). The calibrationcurves(y=3311.4x+45.634) are linear at ranges of 0.100ug～2.000ug(forRutaecarpine, r=0.9999), The content was 2.4%, the average recoveries were100.85%(RSD=1.64%,n=5). The calibration curves(y=157.65x+8.56) are linear atranges of 2.810ug～8.430ug(for Limonin, r=0.9999), The content was 35.70%, theaverage recoveries were 98.81%(RSD=1.29%,n=5). So the content of threealkaloids was 40%, considering the response value. It is convenience for us toanalyze it, only using Rutaecarpine as reference substance.
Chapter 7 In this part we established HPLC fingerprint of the effectivefraction of Rhizoma Coptidis and Fructus Evodiae. So we can accurately controlthe overall quality of effective fraction with fingerprint.
Chapter 8 In this part, we researched on preparation technology ofdropping pills made of effective fraction of Zuojin Wan. And we established thequality standard of the dropping pill using the method of HPLC.
Chapter 9 analysis and summary
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