柘树总黄酮的质量标准及制剂研究
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摘要
柘树Cudrania tricuspidata(Carr.)Bur.为桑科(Moraceae)柘属植物,其根入药,具有祛风除湿、活血通经、健脾益胃等功效,临床多用于治疗风湿关节痛、跌打损伤、脾虚泄泻及黄疸等症,又可用于治疗胃癌等消化系统肿瘤。八十年代初,上海中药二厂将柘树根的提取液制成糖浆剂,用于治疗消化道恶性肿瘤,虽有一定疗效,但该制剂存在活性成分不明确,服用不方便,产品质量的稳定性差等缺点。我们前期的研究工作表明,柘树□山酮乙、macluraxanthoneB和柘树□山酮丁等黄酮类化合物是柘树的抗肿瘤有效成分,并研究了以黄酮类化合物作为有效部位的柘树总黄酮的提取纯化工艺。体内外药效学研究表明该提取物具有显著的抗肿瘤活性,并在联合化疗药增效方面,效果显著,具有良好的开发前景。因此,本论文在原有工作基础上,重点对柘树总黄酮的质量标准及其制剂进行研究,制订了柘树总黄酮及其制剂的质量标准草案,得到了成本经济、体外溶出好、符合《中国药典》要求的口服制剂。
1柘树总黄酮的质量标准研究
以3批实验室放大实验得到的柘树总黄酮为研究对象,以《中国药典》2005年版一部为参照标准,对柘树总黄酮进行了性状、鉴别(化学鉴别、薄层色谱鉴别)、检查(干燥失重、水分、炽灼残渣、重金属、砷盐)等项目的质量标准研究;以柘树□山酮乙、macluraxanthone B和柘树□山酮丁为对照品,建立了高效液相色谱法,对柘树总黄酮中3个异戊烯基□山酮的含量标准进行了研究,以柘树□山酮乙为对照品,建立了紫外-可见分光光度法,对柘树总黄酮中总黄酮的含量标准进行了研究。
首次起草了《柘树总黄酮的质量标准草案及起草说明》。
通过影响因素试验、加速试验和初步稳定性试验,对柘树总黄酮的稳定性作了研究。结果表明,柘树总黄酮性质稳定。
2柘树总黄酮片剂研究
本文首次通过单因素考察和星点设计-效应面法优化柘树总黄酮片剂处方,最终得到了较理想的处方(以制备柘树总黄酮片1000片计):柘树总黄酮100g,微晶纤维素40 g,乳糖70 g,预胶化淀粉60 g,交联聚维酮30 g,4%聚维酮95%乙醇溶液33 mL,硬脂酸镁1.5 g。通过处方优化得到的片剂硬度在70 N以上,崩解时限小于1min,45 min溶出度以柘树口山酮乙、macluraxanthone B和柘树□山酮丁计均大于70%。
对片剂进行了性状、鉴别(化学鉴别、薄层色谱鉴别)、检查(外观、重量差异、硬度、崩解时限、溶出度)、含量测定(与柘树总黄酮含量测定方法一致,也测定了片剂中化合物柘树□山酮乙、macluraxanthone B和柘树□山酮丁和总黄酮的含量)等项目的质量标准研究。
首次起草了《柘树总黄酮片剂的质量标准及起草说明》。
通过影响因素试验、加速试验和初步稳定性试验,对柘树总黄酮片剂的稳定性作了研究。结果表明,柘树总黄酮片剂性质稳定。
3柘树总黄酮固体分散体胶囊剂研究
本文首次研究了柘树总黄酮固体分散体的制备工艺。通过单因素考察选择聚维酮作为固体分散体的载体,比较了溶剂-熔融法和溶剂法制备固体分散体。柘树总黄酮制备成固体分散体后溶出速度显著加快,化合物柘树□山酮乙、macluraxanthone B和柘树□山酮丁的溶出度也显著增加。将柘树总黄酮固体分散体直接装空心胶囊制得胶囊剂。
对胶囊剂进行了性状、鉴别(化学鉴别、薄层色谱鉴别)、检查(外观、水分、装量差异、溶出度)、含量测定(与柘树总黄酮含量测定方法一致,也测定了胶囊剂中化合物柘树□山酮乙、macluraxanthone B和柘树□山酮丁和总黄酮的含量)等项目的质量标准研究。
首次起草了《柘树总黄酮固体分散体胶囊剂的质量标准及起草说明》。
通过影响因素试验、加速试验和初步稳定性试验,对柘树总黄酮固体分散体胶囊剂的稳定性作了研究。结果表明,柘树总黄酮固体分散体胶囊剂性质稳定。
4最后本文对固体分散技术在中药制剂中的应用进行了综述。
Cudrania species(Moraceae),a rich source of prenylated xanthones and flavonoids,have been investigated phytochemically and biologically.Its roots are applied in clinic for the treatment of digestive apparatus tumor,especially gastric carcinoma,and are also used as Chinese folk medicine "Chuan-po-shi" together with the roots of C.cochinchinensis(Lour) against gonorrhea,rheumatism,jaundice,boils, scabies,bruising,and dysmenorrhea.In early 1980s,Zhemu syrups was made from it's root extract for the treatment of gastrointestinal cancer.But its active ingredients were not clear and quality was instable.Our preliminary research showed that prenylated xanthones such as cudratricusxanthones B,D and macluraxanthone B were anti-tumor active ingredients,and also the extraction and purification process of the total flavonoids of C.tricuspidata(CTP) has been investigated.The pharmacological studies showed that CTP had significant anti-tumor activity,and the effect could be improved remarkably combined with chemotherapy drugs.Therefore, on the basis of the previous results,the present study focuses on the quality standards of CTP and its preparations.
1 Researches on the quality standard of CTP
In accordance with Chinese Pharmacopoeia 2005(VolumeⅠ),the quality standard of CTP was researched.CTP was identified by chemical reaction and thin layer chromatography(TLC).General testing methods had been carried out,such as limit test for heavy metals and arsenic,determination of loss on drying and water,etc. The contents of total flavonoids and three prenylated xanthones were determined. Total flavonoids,calculated as cudratricusxanthone B,was determined by colourimetry.Three prenylated xanthones,cudratricusxanthones B,D and macluraxanthone B,were determined by HPLC.According to the experimental results,the quality standard of CTP has been drafted.
The results of the stability experiments showed that CTP was stable under the conditions of 60℃,RH 92.5%and 4500 Lx±500 Lx for at least 10 days, respectively.And CTP was stable after being placed at 40℃,RH 75%and at room temperature for 3 months.
2 Researches on CTP tablets
The formulation of CTP tablets was optimized by single factor and central composite design-response surface methodology.Optimal formulation was proposed to contain CTP 100 g,MCC 40 g,lactose 70 g,PS 60 g,PVPP 30 g,4%PVP 33 mL, and MS 1.5 g.After optimizing,tablets hardness was more than 70 N,disintegration time was less than 1 min,and dissolution of cudratricusxanthones B,D and macluraxanthone B at 45 min were all more than 70%.
The quality standard of CTP tablets was established,including identification (chemical reaction and TLC),inspection(weight variation,hardness,disintegration time,and dissolution),and determination of three prenylated xanthones and total flavonoids.
The results of the stability experiments showed that CTP tablets were stable under the accelerated conditions and room temperature,etc.
3 Researches on CTP solid dispersion capsules
PVP was chosen as solid dispersion carrier by single factor experiment,and the preparation methods of solvent melting and solvent evaporation were compared.The dissolution rate was accelerated significantly after CTP was prepared to solid dispersion,and the dissolution of cudratricusxanthones B,D and macluraxanthone B at 45 min were also increased remarkably.
The quality standard of CTP solid dispersion capsules was established,including identification(chemical reaction and TLC),inspection(water determination,filling variation,and dissolution),and determination of three prenylated xanthones and total flavonoids.
The results of the stability experiments showed that CTP solid dispersion capsules were stable under the accelerated conditions and room temperature,etc.
4 Review
In the end,a review on application of the technology of solid dispersions in the preparations of traditional Chinese medicine is presented.
1柘树总黄酮的质量标准研究
以3批实验室放大实验得到的柘树总黄酮为研究对象,以《中国药典》2005年版一部为参照标准,对柘树总黄酮进行了性状、鉴别(化学鉴别、薄层色谱鉴别)、检查(干燥失重、水分、炽灼残渣、重金属、砷盐)等项目的质量标准研究;以柘树□山酮乙、macluraxanthone B和柘树□山酮丁为对照品,建立了高效液相色谱法,对柘树总黄酮中3个异戊烯基□山酮的含量标准进行了研究,以柘树□山酮乙为对照品,建立了紫外-可见分光光度法,对柘树总黄酮中总黄酮的含量标准进行了研究。
首次起草了《柘树总黄酮的质量标准草案及起草说明》。
通过影响因素试验、加速试验和初步稳定性试验,对柘树总黄酮的稳定性作了研究。结果表明,柘树总黄酮性质稳定。
2柘树总黄酮片剂研究
本文首次通过单因素考察和星点设计-效应面法优化柘树总黄酮片剂处方,最终得到了较理想的处方(以制备柘树总黄酮片1000片计):柘树总黄酮100g,微晶纤维素40 g,乳糖70 g,预胶化淀粉60 g,交联聚维酮30 g,4%聚维酮95%乙醇溶液33 mL,硬脂酸镁1.5 g。通过处方优化得到的片剂硬度在70 N以上,崩解时限小于1min,45 min溶出度以柘树口山酮乙、macluraxanthone B和柘树□山酮丁计均大于70%。
对片剂进行了性状、鉴别(化学鉴别、薄层色谱鉴别)、检查(外观、重量差异、硬度、崩解时限、溶出度)、含量测定(与柘树总黄酮含量测定方法一致,也测定了片剂中化合物柘树□山酮乙、macluraxanthone B和柘树□山酮丁和总黄酮的含量)等项目的质量标准研究。
首次起草了《柘树总黄酮片剂的质量标准及起草说明》。
通过影响因素试验、加速试验和初步稳定性试验,对柘树总黄酮片剂的稳定性作了研究。结果表明,柘树总黄酮片剂性质稳定。
3柘树总黄酮固体分散体胶囊剂研究
本文首次研究了柘树总黄酮固体分散体的制备工艺。通过单因素考察选择聚维酮作为固体分散体的载体,比较了溶剂-熔融法和溶剂法制备固体分散体。柘树总黄酮制备成固体分散体后溶出速度显著加快,化合物柘树□山酮乙、macluraxanthone B和柘树□山酮丁的溶出度也显著增加。将柘树总黄酮固体分散体直接装空心胶囊制得胶囊剂。
对胶囊剂进行了性状、鉴别(化学鉴别、薄层色谱鉴别)、检查(外观、水分、装量差异、溶出度)、含量测定(与柘树总黄酮含量测定方法一致,也测定了胶囊剂中化合物柘树□山酮乙、macluraxanthone B和柘树□山酮丁和总黄酮的含量)等项目的质量标准研究。
首次起草了《柘树总黄酮固体分散体胶囊剂的质量标准及起草说明》。
通过影响因素试验、加速试验和初步稳定性试验,对柘树总黄酮固体分散体胶囊剂的稳定性作了研究。结果表明,柘树总黄酮固体分散体胶囊剂性质稳定。
4最后本文对固体分散技术在中药制剂中的应用进行了综述。
Cudrania species(Moraceae),a rich source of prenylated xanthones and flavonoids,have been investigated phytochemically and biologically.Its roots are applied in clinic for the treatment of digestive apparatus tumor,especially gastric carcinoma,and are also used as Chinese folk medicine "Chuan-po-shi" together with the roots of C.cochinchinensis(Lour) against gonorrhea,rheumatism,jaundice,boils, scabies,bruising,and dysmenorrhea.In early 1980s,Zhemu syrups was made from it's root extract for the treatment of gastrointestinal cancer.But its active ingredients were not clear and quality was instable.Our preliminary research showed that prenylated xanthones such as cudratricusxanthones B,D and macluraxanthone B were anti-tumor active ingredients,and also the extraction and purification process of the total flavonoids of C.tricuspidata(CTP) has been investigated.The pharmacological studies showed that CTP had significant anti-tumor activity,and the effect could be improved remarkably combined with chemotherapy drugs.Therefore, on the basis of the previous results,the present study focuses on the quality standards of CTP and its preparations.
1 Researches on the quality standard of CTP
In accordance with Chinese Pharmacopoeia 2005(VolumeⅠ),the quality standard of CTP was researched.CTP was identified by chemical reaction and thin layer chromatography(TLC).General testing methods had been carried out,such as limit test for heavy metals and arsenic,determination of loss on drying and water,etc. The contents of total flavonoids and three prenylated xanthones were determined. Total flavonoids,calculated as cudratricusxanthone B,was determined by colourimetry.Three prenylated xanthones,cudratricusxanthones B,D and macluraxanthone B,were determined by HPLC.According to the experimental results,the quality standard of CTP has been drafted.
The results of the stability experiments showed that CTP was stable under the conditions of 60℃,RH 92.5%and 4500 Lx±500 Lx for at least 10 days, respectively.And CTP was stable after being placed at 40℃,RH 75%and at room temperature for 3 months.
2 Researches on CTP tablets
The formulation of CTP tablets was optimized by single factor and central composite design-response surface methodology.Optimal formulation was proposed to contain CTP 100 g,MCC 40 g,lactose 70 g,PS 60 g,PVPP 30 g,4%PVP 33 mL, and MS 1.5 g.After optimizing,tablets hardness was more than 70 N,disintegration time was less than 1 min,and dissolution of cudratricusxanthones B,D and macluraxanthone B at 45 min were all more than 70%.
The quality standard of CTP tablets was established,including identification (chemical reaction and TLC),inspection(weight variation,hardness,disintegration time,and dissolution),and determination of three prenylated xanthones and total flavonoids.
The results of the stability experiments showed that CTP tablets were stable under the accelerated conditions and room temperature,etc.
3 Researches on CTP solid dispersion capsules
PVP was chosen as solid dispersion carrier by single factor experiment,and the preparation methods of solvent melting and solvent evaporation were compared.The dissolution rate was accelerated significantly after CTP was prepared to solid dispersion,and the dissolution of cudratricusxanthones B,D and macluraxanthone B at 45 min were also increased remarkably.
The quality standard of CTP solid dispersion capsules was established,including identification(chemical reaction and TLC),inspection(water determination,filling variation,and dissolution),and determination of three prenylated xanthones and total flavonoids.
The results of the stability experiments showed that CTP solid dispersion capsules were stable under the accelerated conditions and room temperature,etc.
4 Review
In the end,a review on application of the technology of solid dispersions in the preparations of traditional Chinese medicine is presented.
引文
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[1]韩 刚,王传胜,张 永.金光灿固体分散体提高姜黄素溶出度的研究[J].中国中药杂志,2007,32(7):637-638
[2]陈 伟,夏 红,吴 伟.星点设计-效应面法优化水飞蓟素滴丸的制备工艺[J].中草药,2005,36(5):679-683
[3]周毅生,贾永艳,申小清,等.葛根素固体分散体的制备及其体外研究[J].中国药学杂志,2003,38(1):42-44
[4]张小莉,王东文.芦丁-PEG_(6000)固体分散体的制备及其溶解性能研究[J].解放军药学报,2000,16(6):306-308
[5]王璐璐,汪仁芸,郑稳生.板蓝根脂溶性成分-PVPK30固体分散体的研究[J].中国新药杂志,2006,16(13):1078-1081
[6]何 丹,杨 林,贺浪冲.白芷香豆素固体分散体的制备及溶出特性研究[J].中成药,2006,28(1):20-23
[7]乔淑娟,金描真,杨 亮.龙血竭固体分散体的制备及其溶出效果的研究[J].广东药学院学报,2007,23(3):263-265
[8]翟光喜.磷脂固体分散体对槲皮素溶出促进作用的研究[J].沈阳药科大学学报,2003,20(4):235
[9]李宝红,张立坚,东野广智.槲皮素聚维酮固体分散体的研制[J].中国药房,2004.15(11):660-661
[10]向大雄,陶昱斐,王 峰,等.齐墩果酸固体分散体形成和增溶机制研究[J].中草药,2002,33(4):311-314
[11]储茂泉,刘 颂,古宏晨,等.丹参酮固体分散物的研究[J].华东理工大学学报,2001,27(2):191
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[13]王 展,韩立炜,任天池.葛根素-聚乙二醇6000固体分散体的制备及其溶解性能的研究[J].北京中医药大学学报,2007,30(5):346-349
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[1]韩 刚,王传胜,张 永.金光灿固体分散体提高姜黄素溶出度的研究[J].中国中药杂志,2007,32(7):637-638
[2]陈 伟,夏 红,吴 伟.星点设计-效应面法优化水飞蓟素滴丸的制备工艺[J].中草药,2005,36(5):679-683
[3]周毅生,贾永艳,申小清,等.葛根素固体分散体的制备及其体外研究[J].中国药学杂志,2003,38(1):42-44
[4]张小莉,王东文.芦丁-PEG_(6000)固体分散体的制备及其溶解性能研究[J].解放军药学报,2000,16(6):306-308
[5]王璐璐,汪仁芸,郑稳生.板蓝根脂溶性成分-PVPK30固体分散体的研究[J].中国新药杂志,2006,16(13):1078-1081
[6]何 丹,杨 林,贺浪冲.白芷香豆素固体分散体的制备及溶出特性研究[J].中成药,2006,28(1):20-23
[7]乔淑娟,金描真,杨 亮.龙血竭固体分散体的制备及其溶出效果的研究[J].广东药学院学报,2007,23(3):263-265
[8]翟光喜.磷脂固体分散体对槲皮素溶出促进作用的研究[J].沈阳药科大学学报,2003,20(4):235
[9]李宝红,张立坚,东野广智.槲皮素聚维酮固体分散体的研制[J].中国药房,2004.15(11):660-661
[10]向大雄,陶昱斐,王 峰,等.齐墩果酸固体分散体形成和增溶机制研究[J].中草药,2002,33(4):311-314
[11]储茂泉,刘 颂,古宏晨,等.丹参酮固体分散物的研究[J].华东理工大学学报,2001,27(2):191
[12]李国栋,周 全,赵长文,等.青蒿素固体分散物的制备及体外溶出研究[J].中国药学杂志,1999,34(1):26-29
[13]王 展,韩立炜,任天池.葛根素-聚乙二醇6000固体分散体的制备及其溶解性能的研究[J].北京中医药大学学报,2007,30(5):346-349
[14]李砥辉,贾玉玺,黄晓洁,等.黄芩苷共沉淀物和固体分散物的生物利用度的研究[J].第四军医大学学报吉林医学院学报,2000,22(1):16
[15]廖海均,刘皋林.水飞蓟宾固体分散体胶囊的人体生物利用度[J].第二军医大学学报,2000,21(10):965
[16]宫曙光,周 全,孙其荣,等.桂甘控释胶囊的制备及体外溶出度的研究[J].中国药业,1996,(9):34
[17]杜 江,丁宁,贾宪生,等.黄褐毛忍冬总皂苷的固体分散体的制备及释放度考察[J].中国中药杂志,2002,27(7):513
[18]李国栋,周 全,赵长文,等.青蒿素缓释固体分散物的制备及其体外溶出研究[J].解放军药学学报,2000,16(1):16-18
[19]尹崇道.蒿甲醚固体分散体缓释制剂的研制及其体外溶出度的观察[J].中国药房,1997,8(6):251
[20]储茂泉,古宏晨,刘国杰,等.丹参酮固体分散体的稳定性[J].华东理工大学学报,2002,28(1):107-109
[21]赵兴红,冯 雷,薛郭渊,等.酸枣仁油滴丸的稳定性初步研究[J].药学实践杂志,1995,13(3):159
[22]詹可顺,魏 伟,余南生.清咽消丸治疗慢性咽炎的临床研究[J].中国基层医药,2003,10(11):1129-1130
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[24]于 莲,郑淑琴,焦淑清,等.三七固体分散体滴丸制备工艺及质量研究[J].黑龙江医药科学,2004,27(6):17-19
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[30]姚 琳,邓康颖.罗佳波肉桂油固体分散体的制备及体外释放[J].南方医科大学学报,2008,28(1):52-56
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[36]杨怡静,平其能,宋簧梅.固体分散体提高银杏叶片溶出度的研究[J].中国新药杂志,2004,13(6):521-524
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