盐酸青藤碱控释微丸的研制及其药物动力学研究
|
摘要
盐酸青藤碱临床主要用于治疗风湿性和类风湿性关节炎，本课题通过对原料药鉴别、控释制剂制备、质量标准、稳定性及生物利用度的研究，完成了盐酸青藤碱控释制剂的临床前研究工作，实验结果均符合中国药典(2000版)的规定。
原料药的紫外扫描图谱、质谱图、特异性鉴别反应及薄层层析图谱研究结果表明，本品在264nm处有最大吸收峰，分子量为329，鉴别反应呈阳性，在供试品色谱中，在与对照品相应位置上显相同颜色的斑点。实验结果与文献报道一致，证明供试品为盐酸青藤碱。
根据盐酸青藤碱的紫外吸收特征，建立了其控释微丸制剂的紫外分光光度法(UV)和反相高效液相色谱法(RP-HPLC)的含量测定方法。通过对线性相关性、精密度、重复性、回收率的测定，结果均符合中国药典的要求。
采用膜控技术，离心包衣造粒法制备了盐酸青藤碱控释微丸。首先采用泛丸法制备丸心，通过对粒径分布、平面临界角、休止角、硬度、脆碎度、水分的测定，对丸心质量进行评价。以Eudragit NE30D水分散体为包衣材料，自制小型沸腾流化床包衣设备对丸心的包衣进行处方筛选。离心造粒机进行工艺放大。以药物溶出性能作为控释指标，筛选最
山西医科大学 硕士学位论文
优控释处方。其次对微丸的体外溶出性能进行了研究，分别考察了港出
介质、溶出装置及不同转速对微丸药物溶出的影响，结果满意。
根据中国药典的规定，对盐酸青藤碱控释微丸的稳定性进行考察，
包括影响因素试验（高温试验、高湿试验、强光照试验）、加速试验和长
期试验。稳定性重点考察项目有微丸外观、特异性鉴别、体外溶出性能。
含量。结果表明，微丸包衣膜对热比较敏感，其他考察项目均稳定。
生物利用度实验中，以大为实验动物，正清风痛宁片为参比制剂，
反相高效液相色谱法（内标法）对生物样品进行测定。3P87动力学软件
拟和动力学参数。结果表明，控释制剂在犬体内血药浓度经时曲线平稳，
维持时间长，无明显的峰谷现象，生物利用度较高，达到了预期的目的。
Sinomenine hydrochloride is used in treatment of rheumatism and rheumatoid. In this paper, the identify of raw material, preparation of controlled-release pellets, quality standard, stability and bioavailbility were studied. The preclinical studies of sinomenine hydrochloride controlled-release preparation were finished. All the experimental results met Chinese pharmacopoeia (edition 2000) regulations.
The material tested was identified as sinomenine hydrochloride according to a maximum absorption peak at 264 nm by ultraviolet scanning pattern, a molecular weight of 299 by mass spectrogram, positive identification reactions, and same Rf and color to reference by TLC.
On the base of characteristics ultraviolet absorption of sinomenine hydrochloride, the ultraviolet spectrophotometry (UV) and reverse-phrase high performance liquid chromatography (RP-HPLC) methods were established for analysis of sinomenine. The linearity, specificity, repeatability and recovery met with the requirements of Chinese pharmacopoeia (edition 2000).
By using membrane controlled-release technique and centrifugal coating pelletization, sinomenine hydrochloride controlled-release pellets were prepared. The first step is to prepare the core of pellets, The partical size distribution, plane critical angle, angle of repose, brittleness, hardness and moisture were used to evaluate the quality of the core of pellets. Eudragit NE30D was used to coating material. A self-designed minitype boiling fluiding bed equipment was used for screening of the coating prescription. The controlled-release efficacy were assessed according to drug dissolution rate. The equipment of centrifugal coating pelletization was used for
magnifying production. The release of pellets were studied with different media, different release equipments and different speeds of revolution.
Followed Chinese pharmacopoeia, the stability of sinomenine hydrochloride controlled-release pellets were studied. Influencing factors including high temperature, high humidity and strong light were investigated. Accelerated test and long-term test were conducted. Appearance of pellets, specific identification reactions, dissolutions and content determination were detected for the stability studies. The results showed that the coating membrane of pellets was sensitive to temperature and stable for other factors. In the bioavailbility experiment, the dogs were used as the experimental animals. Zheng qing feng tong ning tablets was used as the reference. Sinomenine in the biologic samples was analyzed by RP-HPLC. Parameters were estimated by 3P87 pharmacokinetics software. The results showed that the concentration-time curve of sinomenine was flatter, the duration was longer, peak and vale was less obvious than that of reference. Bioavailbility was equivalent. The present studies achieved our prospective aims.
原料药的紫外扫描图谱、质谱图、特异性鉴别反应及薄层层析图谱研究结果表明，本品在264nm处有最大吸收峰，分子量为329，鉴别反应呈阳性，在供试品色谱中，在与对照品相应位置上显相同颜色的斑点。实验结果与文献报道一致，证明供试品为盐酸青藤碱。
根据盐酸青藤碱的紫外吸收特征，建立了其控释微丸制剂的紫外分光光度法(UV)和反相高效液相色谱法(RP-HPLC)的含量测定方法。通过对线性相关性、精密度、重复性、回收率的测定，结果均符合中国药典的要求。
采用膜控技术，离心包衣造粒法制备了盐酸青藤碱控释微丸。首先采用泛丸法制备丸心，通过对粒径分布、平面临界角、休止角、硬度、脆碎度、水分的测定，对丸心质量进行评价。以Eudragit NE30D水分散体为包衣材料，自制小型沸腾流化床包衣设备对丸心的包衣进行处方筛选。离心造粒机进行工艺放大。以药物溶出性能作为控释指标，筛选最
山西医科大学 硕士学位论文
优控释处方。其次对微丸的体外溶出性能进行了研究，分别考察了港出
介质、溶出装置及不同转速对微丸药物溶出的影响，结果满意。
根据中国药典的规定，对盐酸青藤碱控释微丸的稳定性进行考察，
包括影响因素试验（高温试验、高湿试验、强光照试验）、加速试验和长
期试验。稳定性重点考察项目有微丸外观、特异性鉴别、体外溶出性能。
含量。结果表明，微丸包衣膜对热比较敏感，其他考察项目均稳定。
生物利用度实验中，以大为实验动物，正清风痛宁片为参比制剂，
反相高效液相色谱法（内标法）对生物样品进行测定。3P87动力学软件
拟和动力学参数。结果表明，控释制剂在犬体内血药浓度经时曲线平稳，
维持时间长，无明显的峰谷现象，生物利用度较高，达到了预期的目的。
Sinomenine hydrochloride is used in treatment of rheumatism and rheumatoid. In this paper, the identify of raw material, preparation of controlled-release pellets, quality standard, stability and bioavailbility were studied. The preclinical studies of sinomenine hydrochloride controlled-release preparation were finished. All the experimental results met Chinese pharmacopoeia (edition 2000) regulations.
The material tested was identified as sinomenine hydrochloride according to a maximum absorption peak at 264 nm by ultraviolet scanning pattern, a molecular weight of 299 by mass spectrogram, positive identification reactions, and same Rf and color to reference by TLC.
On the base of characteristics ultraviolet absorption of sinomenine hydrochloride, the ultraviolet spectrophotometry (UV) and reverse-phrase high performance liquid chromatography (RP-HPLC) methods were established for analysis of sinomenine. The linearity, specificity, repeatability and recovery met with the requirements of Chinese pharmacopoeia (edition 2000).
By using membrane controlled-release technique and centrifugal coating pelletization, sinomenine hydrochloride controlled-release pellets were prepared. The first step is to prepare the core of pellets, The partical size distribution, plane critical angle, angle of repose, brittleness, hardness and moisture were used to evaluate the quality of the core of pellets. Eudragit NE30D was used to coating material. A self-designed minitype boiling fluiding bed equipment was used for screening of the coating prescription. The controlled-release efficacy were assessed according to drug dissolution rate. The equipment of centrifugal coating pelletization was used for
magnifying production. The release of pellets were studied with different media, different release equipments and different speeds of revolution.
Followed Chinese pharmacopoeia, the stability of sinomenine hydrochloride controlled-release pellets were studied. Influencing factors including high temperature, high humidity and strong light were investigated. Accelerated test and long-term test were conducted. Appearance of pellets, specific identification reactions, dissolutions and content determination were detected for the stability studies. The results showed that the coating membrane of pellets was sensitive to temperature and stable for other factors. In the bioavailbility experiment, the dogs were used as the experimental animals. Zheng qing feng tong ning tablets was used as the reference. Sinomenine in the biologic samples was analyzed by RP-HPLC. Parameters were estimated by 3P87 pharmacokinetics software. The results showed that the concentration-time curve of sinomenine was flatter, the duration was longer, peak and vale was less obvious than that of reference. Bioavailbility was equivalent. The present studies achieved our prospective aims.
引文
1．董建平等 正清风痛宁穴位离子导入治疗类风湿性关节炎30例 中医药学报；1996：(4)：35
2．郝林娜，冷光等 实用临床药物手册 山西医科大学第一医院
3．刘强等 青藤碱的研究概况 中草药，1992；28(4)；247
4．霍海如等 青藤碱镇痛和抗炎机制的研究 西安医科大学学报，1989；10(4)；348
5．李嗣英等 青藤碱对小鼠免疫功能的影响 中草药 1991；23(2)；81
6．赵德化等 盐酸青藤碱的抗心律失常作用 药学学报 1985；20(11)；865
7．傅绍萱等 青藤碱的药理作用 药学通报 1979；7(5)；199
8. Yamasaki H Pharmacology of sinomenine, an anti-rheumatic alkaloid from sinomenine acutum Med Okayama 1976:30(1);1
9. Peng HM Immunosuppressive effects of sinomenine.1988:9(4);377
10．安丰堂等 HPLC 法测定复方中青藤碱的含量研究 中医药学报 1998；(1)；62
11．邱赛红等 青藤碱致突变实验研究 中药药理与临床 1999：15(6)；23
12．闫小华等 HPLC 法测定人血清和尿中青藤碱的浓度及药代动力学研究 药学学报 1997；32(8)；620
13. Lou. S Pharmacokinetics of sinomenine by HPLC KUO CHUNG YAO TSA CHIH 1992:77(7);424
14. Okuda T A case of drug eruption caused by the crude drug sinomenine J. Dermatol 1995:22(10);795
15 毕殿洲 药剂学(第四版) 人民卫生出版社
16 钱方等 微丸的进展 中国医药工业杂志 1996：27(1)；41
17 唐翠等 熔融法制备对乙酰氨基酚缓释微丸 中国医药工业杂志 2000：31(1)；12
18 董志超等 HPMC在凝胶骨架片中的应用 国外医药—合成药、生化药、制剂分册 1999：30(11)；750
19 刘善奎等 盐酸尼卡地平缓释微丸的制备及稳定性研究 中国药学杂志 1999：34(11)；750
20 张玉琥等 扑尔敏缓释微丸的制备及释药动力学研究 中国医药工业杂志 1993：24(4)；538
21 Harris MR 等 缓释制剂的水性材料包衣法 国外药学—合成药、生化药、制剂分册 1988：9(2)；101
22 陈庆华 现代微丸制备与包衣装置的类型与应用 中国医药工业杂志 1996：27(3)；134
23 王柏等 布洛芬缓释微丸的制备及动力学研究 中国药科大学学报 1989：20(5)；266
24 张淑秋 卡托普利控释微丸的研制及其体外释放研究 山西医科大学学报 1997：28
25 陈庆华 复合物作为微丸包衣材料的研究 中国医药工业杂志 1997：27(9)；297(1)；16
26 包泳初 挤出滚圆法制备药用微丸的工艺研究 中国医药工业杂志 1999：30(1)；18
27 刘红萍 盐酸地尔硫卓控释微丸的研制 中国医药工业杂志 1996：27(9)；397
28 陈挺 等 盐酸苯丙胺醇微丸的制备工艺研究 中国医药工业杂志 1999：30(8)；345
29 徐坚 等 甲氧氯普胺液相中球型结聚微丸制备及特性考察 中国医药工业杂志 1996：27(11)；655
30 杨广德等 反相高效液相色谱法测定血浆中青藤碱的含量 中国药学杂志 1993：28(3)；152
31 周建平等 盐酸普萘洛尔控释微丸的研制 中国药科大学学报 1994：25(2)；83
32 朱德湘 正清风痛宁抗风湿作用机理浅谈 湖南中医杂志 1994：10(4)；54
33 尤孝庆等 缓释微丸工艺研究 中国医药工业杂志 1996：27(4)；153
34 陈纪岳等 缓释制剂溶出度测定时间的探讨 中国医药工业杂志 1991：22(2)；69
35 杨令祥等 阿西美辛控制胶囊的研制及释放度研究 中国医院药学杂志 1998：18(1)；20
36 余绍云等 微丸的进展 中国新药杂志 1999；8(12)；803
37 张国华等 控释扑尔敏微丸的研制 中国药科大学学报 1985：16(1)；28
38 中国药典2000版一部
39 施新猷 现代医学实验动物学 人民军医出版社，2000．9
40 李发美 医药高效液相色谱技术 人民卫生出版社，1999
41 陆彬 药物新剂型与新技术 人民卫生出版社，1998
42 丙烯酸聚合物在缓释制剂上的应用 德国罗姆公司
2．郝林娜，冷光等 实用临床药物手册 山西医科大学第一医院
3．刘强等 青藤碱的研究概况 中草药，1992；28(4)；247
4．霍海如等 青藤碱镇痛和抗炎机制的研究 西安医科大学学报，1989；10(4)；348
5．李嗣英等 青藤碱对小鼠免疫功能的影响 中草药 1991；23(2)；81
6．赵德化等 盐酸青藤碱的抗心律失常作用 药学学报 1985；20(11)；865
7．傅绍萱等 青藤碱的药理作用 药学通报 1979；7(5)；199
8. Yamasaki H Pharmacology of sinomenine, an anti-rheumatic alkaloid from sinomenine acutum Med Okayama 1976:30(1);1
9. Peng HM Immunosuppressive effects of sinomenine.1988:9(4);377
10．安丰堂等 HPLC 法测定复方中青藤碱的含量研究 中医药学报 1998；(1)；62
11．邱赛红等 青藤碱致突变实验研究 中药药理与临床 1999：15(6)；23
12．闫小华等 HPLC 法测定人血清和尿中青藤碱的浓度及药代动力学研究 药学学报 1997；32(8)；620
13. Lou. S Pharmacokinetics of sinomenine by HPLC KUO CHUNG YAO TSA CHIH 1992:77(7);424
14. Okuda T A case of drug eruption caused by the crude drug sinomenine J. Dermatol 1995:22(10);795
15 毕殿洲 药剂学(第四版) 人民卫生出版社
16 钱方等 微丸的进展 中国医药工业杂志 1996：27(1)；41
17 唐翠等 熔融法制备对乙酰氨基酚缓释微丸 中国医药工业杂志 2000：31(1)；12
18 董志超等 HPMC在凝胶骨架片中的应用 国外医药—合成药、生化药、制剂分册 1999：30(11)；750
19 刘善奎等 盐酸尼卡地平缓释微丸的制备及稳定性研究 中国药学杂志 1999：34(11)；750
20 张玉琥等 扑尔敏缓释微丸的制备及释药动力学研究 中国医药工业杂志 1993：24(4)；538
21 Harris MR 等 缓释制剂的水性材料包衣法 国外药学—合成药、生化药、制剂分册 1988：9(2)；101
22 陈庆华 现代微丸制备与包衣装置的类型与应用 中国医药工业杂志 1996：27(3)；134
23 王柏等 布洛芬缓释微丸的制备及动力学研究 中国药科大学学报 1989：20(5)；266
24 张淑秋 卡托普利控释微丸的研制及其体外释放研究 山西医科大学学报 1997：28
25 陈庆华 复合物作为微丸包衣材料的研究 中国医药工业杂志 1997：27(9)；297(1)；16
26 包泳初 挤出滚圆法制备药用微丸的工艺研究 中国医药工业杂志 1999：30(1)；18
27 刘红萍 盐酸地尔硫卓控释微丸的研制 中国医药工业杂志 1996：27(9)；397
28 陈挺 等 盐酸苯丙胺醇微丸的制备工艺研究 中国医药工业杂志 1999：30(8)；345
29 徐坚 等 甲氧氯普胺液相中球型结聚微丸制备及特性考察 中国医药工业杂志 1996：27(11)；655
30 杨广德等 反相高效液相色谱法测定血浆中青藤碱的含量 中国药学杂志 1993：28(3)；152
31 周建平等 盐酸普萘洛尔控释微丸的研制 中国药科大学学报 1994：25(2)；83
32 朱德湘 正清风痛宁抗风湿作用机理浅谈 湖南中医杂志 1994：10(4)；54
33 尤孝庆等 缓释微丸工艺研究 中国医药工业杂志 1996：27(4)；153
34 陈纪岳等 缓释制剂溶出度测定时间的探讨 中国医药工业杂志 1991：22(2)；69
35 杨令祥等 阿西美辛控制胶囊的研制及释放度研究 中国医院药学杂志 1998：18(1)；20
36 余绍云等 微丸的进展 中国新药杂志 1999；8(12)；803
37 张国华等 控释扑尔敏微丸的研制 中国药科大学学报 1985：16(1)；28
38 中国药典2000版一部
39 施新猷 现代医学实验动物学 人民军医出版社，2000．9
40 李发美 医药高效液相色谱技术 人民卫生出版社，1999
41 陆彬 药物新剂型与新技术 人民卫生出版社，1998
42 丙烯酸聚合物在缓释制剂上的应用 德国罗姆公司