升血小板分散片的研制
|
摘要
升血小板分散片是由升血小板胶囊改剂型而来。升血小板胶囊是一种专门用于治疗免疫性血小板减少性紫癜(ITP)的纯中药制剂,其主要成分为青黛、连翘、仙鹤草、牡丹皮和甘草,具有清热解毒、凉血止血、散瘀消斑的作用,临床验证其疗效确切。但是由于胶囊体积较大,或一次常需多粒给药,给患者特别是老人、儿童和吞咽固体存在困难的病人的治疗带来了困难。本课题在保持原有处方药味的基础上,对升血小板胶囊进行了二次开发研究,将其制成分散片,使其更适应临床用药的要求。
根据处方药物所含成分的理化性质,结合实际生产及具体情况,分别进行了连翘药材挥发油提取工艺的考察、牡丹皮和仙鹤草醇提工艺的考察、连翘和甘草水提工艺的考察,并分别以其中的主要成分作为参考指标,对提取方法进行了进一步的筛选优化。
结合提取物的性质,对分散片处方中的填充剂、崩解剂、助流剂等的种类、配比、加入方法进行了考察,确定了优化后分散片的制剂处方和制备工艺。在分散片质量研究中,进行了青黛、连翘和牡丹皮的薄层色谱鉴别;对崩解时间、硬度、溶出度等进行了控制;建立了指标成分靛玉红的HPLC含量测定方法并进行了方法学研究,结果证明HPLC法灵敏度高、专属性好、操作简易。对试验制得的升血小板分散片进行了初步的稳定性试验和加速试验,结果表明分散片从外观到内在质量均具有良好的稳定性。
Shengxuexiaoban dispersible table is a new dosage form and its prescription is based on the commercial capsule.Shengxuexiaoban capsule is a kind of traditional Chinese medicine preparation which is used for the treatment of immunologic thrombocytopenic Purpura(ITP),the main ingredients in the preparation are composed of Indigo Naturalis,Frutus Forsythiae,Herba Agrimoniae,Cortex Moutan and Radix Glycytthizae.The pharmacological effects of Shengxuexiaoban capsule include heat-clearing and detoxifying,cooling blood to stop bleeding, eliminating stasis to activate blood circulation and macula.However,relatively large volume or several pills in one time leads to many difficulties for patients,especially elderly,children and patients who are difficult in swallowing solid.Based on the original prescription,dispersible tablet which is more suitably for the clinic requirements is developed in the study.
According to the physicochemical properties of ingredients in the prescription and actually manufacturing conditions,the extraction technology for Frutus Forsythiae,Cortex Moutan,Herba Agrimoniae,Frutus Forsythiae and Radix Glycyrrhizae was studied,respectively,and the extract methods were optimized on the basis of main effective component.
Combined the characters of the extracts,the kinds,ratios and adding methods of bulking agents,disintegrating agents and glidant agents in the prescription of dispersible tablet were investigated and then the preparing technology were obtained.
In the study on the quality of dispersible tablets,the identification of Indigo Naturalis,Frutus Forsythiae and Cortex Moutan was performed with the method of TLC.The parameters such as disintegration time,hardness and dissolution were set as quality control index.A high sensitive and specific HPLC for the assay of Indirubin was established.
The results of preliminary stability test of Shengxuexiaoban dispersible tablets showed that the dispersible tablets had good stability during 12 months.
根据处方药物所含成分的理化性质,结合实际生产及具体情况,分别进行了连翘药材挥发油提取工艺的考察、牡丹皮和仙鹤草醇提工艺的考察、连翘和甘草水提工艺的考察,并分别以其中的主要成分作为参考指标,对提取方法进行了进一步的筛选优化。
结合提取物的性质,对分散片处方中的填充剂、崩解剂、助流剂等的种类、配比、加入方法进行了考察,确定了优化后分散片的制剂处方和制备工艺。在分散片质量研究中,进行了青黛、连翘和牡丹皮的薄层色谱鉴别;对崩解时间、硬度、溶出度等进行了控制;建立了指标成分靛玉红的HPLC含量测定方法并进行了方法学研究,结果证明HPLC法灵敏度高、专属性好、操作简易。对试验制得的升血小板分散片进行了初步的稳定性试验和加速试验,结果表明分散片从外观到内在质量均具有良好的稳定性。
Shengxuexiaoban dispersible table is a new dosage form and its prescription is based on the commercial capsule.Shengxuexiaoban capsule is a kind of traditional Chinese medicine preparation which is used for the treatment of immunologic thrombocytopenic Purpura(ITP),the main ingredients in the preparation are composed of Indigo Naturalis,Frutus Forsythiae,Herba Agrimoniae,Cortex Moutan and Radix Glycytthizae.The pharmacological effects of Shengxuexiaoban capsule include heat-clearing and detoxifying,cooling blood to stop bleeding, eliminating stasis to activate blood circulation and macula.However,relatively large volume or several pills in one time leads to many difficulties for patients,especially elderly,children and patients who are difficult in swallowing solid.Based on the original prescription,dispersible tablet which is more suitably for the clinic requirements is developed in the study.
According to the physicochemical properties of ingredients in the prescription and actually manufacturing conditions,the extraction technology for Frutus Forsythiae,Cortex Moutan,Herba Agrimoniae,Frutus Forsythiae and Radix Glycyrrhizae was studied,respectively,and the extract methods were optimized on the basis of main effective component.
Combined the characters of the extracts,the kinds,ratios and adding methods of bulking agents,disintegrating agents and glidant agents in the prescription of dispersible tablet were investigated and then the preparing technology were obtained.
In the study on the quality of dispersible tablets,the identification of Indigo Naturalis,Frutus Forsythiae and Cortex Moutan was performed with the method of TLC.The parameters such as disintegration time,hardness and dissolution were set as quality control index.A high sensitive and specific HPLC for the assay of Indirubin was established.
The results of preliminary stability test of Shengxuexiaoban dispersible tablets showed that the dispersible tablets had good stability during 12 months.
引文
[1]张之南,单渊东,李蓉生,等.协和血液病学.北京:中国协和医科大学出版社,2004,626
[2]Cines DB,McMillan R.Management of adult idiopathic thrombocytopenic purpura[J].Annu RevMed,2005,56:425-442
[3]McMillan R.Classical management of refractory adult immune(idiopathic)thrombocytopenic purpura[J].Blood Rev,2002,16:51-55
[4]Gemsheimer T.Pathophysiology and thrombokinetics in autoimmune thrombocytopenia [J].Blood Rev,2002,16:7
[5]刘卓刚,臧师竹.病毒感染引起血小板减少性紫癜的主要机制[J].中国实用内科杂志,2002,22(3):138-139
[6]王彦,王笑蕾.病毒感染与特发性血小板减少性紫癜[J].医学综述,2008,14(3):445-447
[7]高举,罗春华.自身免疫性血小板减少性紫癜的发病机制及诊疗进展[J].中国实用儿科杂志,2003,18(2):77-79
[8]刘家华,徐军发,钟明,等.CD_4~+CD_(25)~+调节性T细胞在免疫性血小板减少性紫癜中的调节作用[J].临床内科杂志,2006,23(6):382-384
[9]苏丽萍,郝国平,罗鹏飞,等.慢性特发性血小板减少性紫癜患者细胞免疫功能的研究[J].中华血液学杂志,2000,21(3):144-145
[10]卢俊,柴忆欢.儿童免疫性血小板减少性紫癜发病因素分析[J].苏州大学学报,2005,25(1):131-132
[11]吴润晖,马洁,周翾,等.儿童特发性血小板减少性紫癜疾病演变的探讨[J].中国小儿血液与肿瘤杂志,2008,13(2):10-13
[12]王学文.成人慢性免疫性血小板减少性紫癜的治疗进展[J].医学研究生学报,2003,1(1):51-53
[13]滕熔,徐瑞容.血浆置换治疗免疫性血小板减少性紫癜[J].中国血液流变学杂志,2004,14(2):267-268
[14]侯明,秦平.免疫性血小板减少性紫癜的诊断及治疗[J].中国实用内科杂志,2006,26(7):489-492
[15]George JN,Woolf SH,Raskob GE,et al.Idiopathic thrombo-cytopenic purpura:A practice guideline developed by explicit methods for the American Society of Hematology[J].Blood,1996,88(1):3-40
[16]Lee GR,Foerster J,Lukens J,et al.Wintrobe's Clinical Hematology[M].Canada:Lipincott Williams & Wilkins,1999,1592-1593
[17]曹志扬.联合用药治疗难治性血小板减少性紫癜[J].检验医学与临床,2007,4(12):1248-1249
[18]李绪香.大剂量甲基强的松龙与静脉输注免疫球蛋白治疗急性血小板减少性紫癜临床观察[J].药物与临床,2006,3(35):69-70
[19]李焱.中西医结合治疗特发性血小板减少性紫癜临床分析[J].现代中西医结合杂志,2007,16(8):1074
[20]李珍,沈一平,周郁鸿.中西医结合治疗特发性血小板减少性紫癜概况及评析[J].浙江中医药大学学,2007,31(2):245-246
[21]伍振峰,何伟.中药分散片的研究概况[J].食品与药品,2008,10(5):69-72
[22]陆彬.药剂学.北京:中国医药科技出版社,2003,202
[23]British Pharmacopoeia Commission.British Pharmacopoeia[S].London:HMSO,1993:779,849,858
[24]中华人民共和国国家药典委员会.中国药典[S].二部.北京:化学工业出版社,2005:167,293,337,678,757
[25]宋民宪,郭维加.新编国家中成药.人民卫生出版社,2002,379
[26]白洁,何应.当归分散片处方与直接压片工艺的研究[J],医药导报,2008,27(3):315-318
[27]李健,李峰,张爱均.肺宁分散片的提取工艺优选及成型工艺研究[J].山东中医药大学学报,2008,32(2):145-147
[28]简晓顺,徐月红,王栋.金刚藤分散片的制备工艺及质量标准研究[J].2008,24(1):47-50
[29]郭涛,宋洪涛,赵明宏.麝香保心分散片的制备及其冰片和人参总皂昔的体外溶出度研究.中国药学杂志,2002,37(11):836
[30]董磊,刘帅英,韩培海.中药分散片处方设计及制备工艺研究进展[J].江西中 医药,2007,28(290):59-61
[31]汤继辉,胡容峰,怀素丽.新型辅料性质考察及其在中药分散片中的应用[J].中国中医药科技,2008,15(1):48-49
[32]陈志明,陆伟根,王大林,等.分散片制备技术[J].中国医药工业杂志,2004,35(6):371-381
[33]陈趋源,刘振香.分散片处方研究与制备工艺[J].齐鲁药事,2007,26(1):39-41
[34]张莹,王丽云,张榜继.表面活性剂在分散片中的应用[J].中国药业,2002,11(12):48
[35]杜青,郑宁,孙鹏,等.阿莫西林分散片的制各及性质考察[J].河北医科大学学报,2000,21(3):135
[36]许亚梅,李冬云,陈信义.难治性血小板减少性紫癜中医治疗初探[J].北京教育学院学报,2006,1(2):31-34
[37]李杨,曲道炜,马骥.特发性血小板减少性紫癜的中医病因病机探要[J].辽宁中医杂志,2007,34(5):574-575
[38]张介宾.景岳全书[M].上海:上海科学技术出版社,1959:515
[39]李杨,马骥.特发性血小板减少性紫癜辩证探讨[J].中国中医药信息杂志,2008,15(3):87-88
[40]汪亮,刘显银,赵俊.中药对血小板减少性紫癜的治疗作用及作用机理研究进展[J].辽宁中医药大学学报,2007,9(2):37-39
[41]林琳,甘欣锦.中医药治疗特发性血小板减少性紫癜研究进展[J].实用中医内科杂志,2007,21(1):26-27
[42]郑家玲,郑臣友,房云霞.青黛的药用价值[J].哈尔滨医药,2005,25(6):86
[43]张健萍,李连珍,赵红江,等.牡丹皮的化学成分、药理作用及临床应用研究概况[J].中华中医药杂志,2006,21(5):295-297
[44]胡竟一,雷玲,余悦,等.连翘的抗炎解热作用研究[J].中药药理与临床,2007,23(3):51-52
[45]杨月妍.重用连翘治疗紫癜临证经验举隅[J].实用中医内科杂志,2007,21 (10):66
[46]张东,邬国栋,张述禹.仙鹤草的药理和临床研究新进展[J].中国药业,2004,13(6):79-80
[47]孙志华,王会朋,关旭鸥,等.活血化瘀清热解毒法治疗难治性血小板减少性紫癜临床观察[J].中国实用医药,2007,2(20):76-77
[48]刘凌,冯莹,庞缨,等.升血小板胶囊治疗特发性血小板减少性紫癜的疗效观察[J].中国医院用药评价与分析,2004,4(4):233-235
[49]胡小月,程熠,王芳.升血小板胶囊治疗儿童特发性血小板减少性紫癜的作用观察[J].华中医学杂志,2008,32(4):273-274
[50]于天启,戴嬍,杨宏光等.升血小板胶囊为主综合治疗难治性血小板减少性紫癜15例疗效观察[J].新中医,2007,39(3):31-32
[51]胡红宇,杨郁,于能江,等.牡丹皮化学成分研究[J].中国中药杂志,2006,31(21):1793-1795
[52]吕英刚,刘世安,吴敏菊,等.山东贯叶连翘挥发油成分分析[J].中国中医药信息杂志,2007,14(8):42-43
[53]王娅丽,杨建雄,柴渭莉.连翘叶中连翘苷类成分的提取工艺研究[J].西北药学杂志,2006,21(1):9-10
[54]徐翔,龚瑛.发达国家中药质量标准和我国的中药现代化[J].上海中医药杂志,2006,40(3):50-51
[55]李文.青黛及其两种伪品的鉴别[J].中成药,2007,29(2):293-295
[56]谢芳.靛玉红提取分离及含量测定的研究[J].云南中医中药杂志,2008,29(4):46-47
[2]Cines DB,McMillan R.Management of adult idiopathic thrombocytopenic purpura[J].Annu RevMed,2005,56:425-442
[3]McMillan R.Classical management of refractory adult immune(idiopathic)thrombocytopenic purpura[J].Blood Rev,2002,16:51-55
[4]Gemsheimer T.Pathophysiology and thrombokinetics in autoimmune thrombocytopenia [J].Blood Rev,2002,16:7
[5]刘卓刚,臧师竹.病毒感染引起血小板减少性紫癜的主要机制[J].中国实用内科杂志,2002,22(3):138-139
[6]王彦,王笑蕾.病毒感染与特发性血小板减少性紫癜[J].医学综述,2008,14(3):445-447
[7]高举,罗春华.自身免疫性血小板减少性紫癜的发病机制及诊疗进展[J].中国实用儿科杂志,2003,18(2):77-79
[8]刘家华,徐军发,钟明,等.CD_4~+CD_(25)~+调节性T细胞在免疫性血小板减少性紫癜中的调节作用[J].临床内科杂志,2006,23(6):382-384
[9]苏丽萍,郝国平,罗鹏飞,等.慢性特发性血小板减少性紫癜患者细胞免疫功能的研究[J].中华血液学杂志,2000,21(3):144-145
[10]卢俊,柴忆欢.儿童免疫性血小板减少性紫癜发病因素分析[J].苏州大学学报,2005,25(1):131-132
[11]吴润晖,马洁,周翾,等.儿童特发性血小板减少性紫癜疾病演变的探讨[J].中国小儿血液与肿瘤杂志,2008,13(2):10-13
[12]王学文.成人慢性免疫性血小板减少性紫癜的治疗进展[J].医学研究生学报,2003,1(1):51-53
[13]滕熔,徐瑞容.血浆置换治疗免疫性血小板减少性紫癜[J].中国血液流变学杂志,2004,14(2):267-268
[14]侯明,秦平.免疫性血小板减少性紫癜的诊断及治疗[J].中国实用内科杂志,2006,26(7):489-492
[15]George JN,Woolf SH,Raskob GE,et al.Idiopathic thrombo-cytopenic purpura:A practice guideline developed by explicit methods for the American Society of Hematology[J].Blood,1996,88(1):3-40
[16]Lee GR,Foerster J,Lukens J,et al.Wintrobe's Clinical Hematology[M].Canada:Lipincott Williams & Wilkins,1999,1592-1593
[17]曹志扬.联合用药治疗难治性血小板减少性紫癜[J].检验医学与临床,2007,4(12):1248-1249
[18]李绪香.大剂量甲基强的松龙与静脉输注免疫球蛋白治疗急性血小板减少性紫癜临床观察[J].药物与临床,2006,3(35):69-70
[19]李焱.中西医结合治疗特发性血小板减少性紫癜临床分析[J].现代中西医结合杂志,2007,16(8):1074
[20]李珍,沈一平,周郁鸿.中西医结合治疗特发性血小板减少性紫癜概况及评析[J].浙江中医药大学学,2007,31(2):245-246
[21]伍振峰,何伟.中药分散片的研究概况[J].食品与药品,2008,10(5):69-72
[22]陆彬.药剂学.北京:中国医药科技出版社,2003,202
[23]British Pharmacopoeia Commission.British Pharmacopoeia[S].London:HMSO,1993:779,849,858
[24]中华人民共和国国家药典委员会.中国药典[S].二部.北京:化学工业出版社,2005:167,293,337,678,757
[25]宋民宪,郭维加.新编国家中成药.人民卫生出版社,2002,379
[26]白洁,何应.当归分散片处方与直接压片工艺的研究[J],医药导报,2008,27(3):315-318
[27]李健,李峰,张爱均.肺宁分散片的提取工艺优选及成型工艺研究[J].山东中医药大学学报,2008,32(2):145-147
[28]简晓顺,徐月红,王栋.金刚藤分散片的制备工艺及质量标准研究[J].2008,24(1):47-50
[29]郭涛,宋洪涛,赵明宏.麝香保心分散片的制备及其冰片和人参总皂昔的体外溶出度研究.中国药学杂志,2002,37(11):836
[30]董磊,刘帅英,韩培海.中药分散片处方设计及制备工艺研究进展[J].江西中 医药,2007,28(290):59-61
[31]汤继辉,胡容峰,怀素丽.新型辅料性质考察及其在中药分散片中的应用[J].中国中医药科技,2008,15(1):48-49
[32]陈志明,陆伟根,王大林,等.分散片制备技术[J].中国医药工业杂志,2004,35(6):371-381
[33]陈趋源,刘振香.分散片处方研究与制备工艺[J].齐鲁药事,2007,26(1):39-41
[34]张莹,王丽云,张榜继.表面活性剂在分散片中的应用[J].中国药业,2002,11(12):48
[35]杜青,郑宁,孙鹏,等.阿莫西林分散片的制各及性质考察[J].河北医科大学学报,2000,21(3):135
[36]许亚梅,李冬云,陈信义.难治性血小板减少性紫癜中医治疗初探[J].北京教育学院学报,2006,1(2):31-34
[37]李杨,曲道炜,马骥.特发性血小板减少性紫癜的中医病因病机探要[J].辽宁中医杂志,2007,34(5):574-575
[38]张介宾.景岳全书[M].上海:上海科学技术出版社,1959:515
[39]李杨,马骥.特发性血小板减少性紫癜辩证探讨[J].中国中医药信息杂志,2008,15(3):87-88
[40]汪亮,刘显银,赵俊.中药对血小板减少性紫癜的治疗作用及作用机理研究进展[J].辽宁中医药大学学报,2007,9(2):37-39
[41]林琳,甘欣锦.中医药治疗特发性血小板减少性紫癜研究进展[J].实用中医内科杂志,2007,21(1):26-27
[42]郑家玲,郑臣友,房云霞.青黛的药用价值[J].哈尔滨医药,2005,25(6):86
[43]张健萍,李连珍,赵红江,等.牡丹皮的化学成分、药理作用及临床应用研究概况[J].中华中医药杂志,2006,21(5):295-297
[44]胡竟一,雷玲,余悦,等.连翘的抗炎解热作用研究[J].中药药理与临床,2007,23(3):51-52
[45]杨月妍.重用连翘治疗紫癜临证经验举隅[J].实用中医内科杂志,2007,21 (10):66
[46]张东,邬国栋,张述禹.仙鹤草的药理和临床研究新进展[J].中国药业,2004,13(6):79-80
[47]孙志华,王会朋,关旭鸥,等.活血化瘀清热解毒法治疗难治性血小板减少性紫癜临床观察[J].中国实用医药,2007,2(20):76-77
[48]刘凌,冯莹,庞缨,等.升血小板胶囊治疗特发性血小板减少性紫癜的疗效观察[J].中国医院用药评价与分析,2004,4(4):233-235
[49]胡小月,程熠,王芳.升血小板胶囊治疗儿童特发性血小板减少性紫癜的作用观察[J].华中医学杂志,2008,32(4):273-274
[50]于天启,戴嬍,杨宏光等.升血小板胶囊为主综合治疗难治性血小板减少性紫癜15例疗效观察[J].新中医,2007,39(3):31-32
[51]胡红宇,杨郁,于能江,等.牡丹皮化学成分研究[J].中国中药杂志,2006,31(21):1793-1795
[52]吕英刚,刘世安,吴敏菊,等.山东贯叶连翘挥发油成分分析[J].中国中医药信息杂志,2007,14(8):42-43
[53]王娅丽,杨建雄,柴渭莉.连翘叶中连翘苷类成分的提取工艺研究[J].西北药学杂志,2006,21(1):9-10
[54]徐翔,龚瑛.发达国家中药质量标准和我国的中药现代化[J].上海中医药杂志,2006,40(3):50-51
[55]李文.青黛及其两种伪品的鉴别[J].中成药,2007,29(2):293-295
[56]谢芳.靛玉红提取分离及含量测定的研究[J].云南中医中药杂志,2008,29(4):46-47