珍珠菜有效部位提取物缓释微丸的研究
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摘要
中药现代化是时代发展的必然要求,中药制剂现代化是中药现代化的前提与基础。本研究根据中医临床用药的需要,以具有抗肿瘤作用的中药珍珠菜为模型药物,采用现代制剂的新方法、新技术、新辅料、新设备,开发研究了一种符合中药特点的中药缓释制剂,并制订科学严格的质量控制标准,使其达到“安全、有效、稳定、可控”,能更有效地发挥中药在防治疾病中的作用特点。
采用紫外分光光度法,建立了珍珠菜有效部位提取物及其制剂的含量和体外释放度的测定方法。此法简便、灵敏、准确,可以满足体内分析的要求。对珍珠菜有效部位提取物理化性质的研究表明,其溶解度随着水溶液pH值的增大而增大,而油水分配系数则随着pH值的增大而减小。提取物在强光、高温条件下稳定性较好。
选用乙醇回流法提取珍珠菜有效部位,在单因素实验的基础上,运用正交设计的方法优化提取工艺。优化工艺为:80%乙醇提取3次,每次12倍量,提取2小时。以饱和吸附量、洗脱百分率以及纯度为指标,考察了三种大孔树脂对有效部位纯化效果的影响。结果表明,AB-8树脂明显优于其它两种树脂。在此基础上,进一步筛选了AB-8树脂对活性部位纯化的最佳条件:上样流速1.0 ml/min、样品液浓度10 mg/ml、样品液pH值5.07。以40%乙醇以1.5ml/min流速洗脱,制得的珍珠菜有效部位提取物中总黄酮含量达25.5%。
采用大鼠在体灌流方案,通过不同肠段的结扎对珍珠菜有效部位提取物中芦丁的吸收部位及吸收百分率进行了研究。实验结果表明,芦丁在各肠道均有吸收,在空肠部位吸收最佳,在肠道内的吸收机制是被动扩散的方式。
制剂部分分为素丸的制备和包缓释衣膜。以HPC为填充剂,由挤出-滚圆法制得素丸。采用流化床包衣技术,以乙基纤维素为主要包衣材料,对影响缓释微丸释放的各因素进行了考察,确定了微丸的包衣液的处方组成和包衣工艺。包衣液采用90%乙醇为溶剂,致孔剂(PEG6000)、抗粘剂(滑石粉)分别占包衣聚合物量的12%、20%。包衣增重为5%,老化时间为24小时。本文对所制缓释微丸的释药机制进行了探讨,结果表明所制微丸均符合一级动力学释药过程。采用相似因子法研究了缓释微丸的稳定性,结果表明缓释微丸在高温、高湿、光照试验条件下性质稳定。
采用高效液相色谱法,建立了家犬体内血药浓度的测定方法。以自制普通微丸胶囊作为参比制剂,研究了缓释微丸胶囊在家犬体内药代动力学。研究表明:缓释微丸胶囊在测定时间范围内血药浓度曲线与速释微丸相比,较为平稳,达峰时间有所延长,峰浓度下降。用非隔室模型统计矩法分析的参数也表明,缓释微丸中药物在体内的平均滞留时间延长,缓释效果较好,体内外相关性良好。
It is necessary to realize the modernization of Chinese traditional medicine to meet the request of the development of times. The modernization of preparation is the premise and base of the modernization of Chinese traditional medicine. In this paper, to adapt the need of clinic, Lysimachia clethroides Duby, the drug of anti-tumor, was selected as the model drug. On base of new method, new technology, new supplements and equipment, a new Chinese traditional medicinal sustained-release preparation was developed, which was accorded with the characteristics of Chinese traditional medicine. To assure the safety, therapeutic, efficiency, stability of the drug, strict quality standard was established, so the preparation could exert action and characteristics in preventing and curing diseases more efficiently.
Ultraviolet spectrophotometry method was developed for assaying during the study of content determination of the drug and release rate of the pellets. The method was accurate, liable, convenient and rapid, which meet the requirement of measurement. In the pre-formulation researches, the physicochemical properties of material drug were investigated, which were connected closely with pharmaceutic form design . The solubility of the drug in different buffer were increased while the apparent oil-water partition coefficient (Papp) decreased with the increase of pH value .In addition, the extract was stable when exposed to light,high temperature.
Extract total flavone from Lysimachia clethroides Duby through ethanol solution. Based on the studies of the influence factors,orthogonal test was used to optimize the extract conditions. The optimized extraction technics was to use 80% alcohol, 3times, 12 quantity and 2 hour per time. Then Three kinds of macro porous adsorbents were used to study adsorption performance for total flavone. The result showed that AB-8 was a kind of good adsorption resin for total flavone. In addition, the optimum conditions were filtered as follows: concentration of total flavone of liquid samples was 10 mg/mL, pH was 5.07, and fluid velocity was 1.0 mL/min, eluted by 40% alcohol at flow speed of 1.5 mL/min, total flavone in ZE4 reached 25.5%.
The absorption sites and the absorption kinetics were studied from various intestinal segments ligation using in situ perfusion method in rats. The research demonstrated that rutin was absorbed in the varied intestinal segments and mostly absorbed in jejunum .The mechanism of the gastrointestinal absorption of rutin was passive diffusion.
The process included the preparation of prompt-release pellets and coating of the pellets. HPC as dilute agent and water as adhesive agent ,the prompt-release pellets were prepared by the method of extrusion-spheronization. A fluid bed spray processor was adopted for coating the pellets. Using EC as coating material, the thesis screened the coating process parameters. The coating process variables were determined and controlled . The pellets was produced by with 90% alcohol and by filtration of a series of poreforming agent PEG6000( 12%), talc( 20%) , coating level( 5%) and curing time(24h).The description of dissolution profiles suggested that among the kinetics, the first-order became the most appropriate model to describe. The stability of the coated pellets was monitored. The results showed the coated pellets were stable under high temperature, high humidity, strong light.
Choosing rutin as standard sample, HPLC with UV detection was applied to analysis the plasma sample in dogs. The methods are accurate, liable, convenient and rapid, which meet the requirement of measurement.Pharmacokinetic studies of sustained-release and prompt-release capsule in dogs were performed based on determination of plasma concentration of drugs. The results showed, compared with prompt-release capsule, plasma concentration of sustained-release capsule was relatively stable, Tmax was postponed and Cmax was lowered and the mean residence time (MRT) was prolonged.The correlation study showed that a good relationship between in vivo and in vitro was built.
采用紫外分光光度法,建立了珍珠菜有效部位提取物及其制剂的含量和体外释放度的测定方法。此法简便、灵敏、准确,可以满足体内分析的要求。对珍珠菜有效部位提取物理化性质的研究表明,其溶解度随着水溶液pH值的增大而增大,而油水分配系数则随着pH值的增大而减小。提取物在强光、高温条件下稳定性较好。
选用乙醇回流法提取珍珠菜有效部位,在单因素实验的基础上,运用正交设计的方法优化提取工艺。优化工艺为:80%乙醇提取3次,每次12倍量,提取2小时。以饱和吸附量、洗脱百分率以及纯度为指标,考察了三种大孔树脂对有效部位纯化效果的影响。结果表明,AB-8树脂明显优于其它两种树脂。在此基础上,进一步筛选了AB-8树脂对活性部位纯化的最佳条件:上样流速1.0 ml/min、样品液浓度10 mg/ml、样品液pH值5.07。以40%乙醇以1.5ml/min流速洗脱,制得的珍珠菜有效部位提取物中总黄酮含量达25.5%。
采用大鼠在体灌流方案,通过不同肠段的结扎对珍珠菜有效部位提取物中芦丁的吸收部位及吸收百分率进行了研究。实验结果表明,芦丁在各肠道均有吸收,在空肠部位吸收最佳,在肠道内的吸收机制是被动扩散的方式。
制剂部分分为素丸的制备和包缓释衣膜。以HPC为填充剂,由挤出-滚圆法制得素丸。采用流化床包衣技术,以乙基纤维素为主要包衣材料,对影响缓释微丸释放的各因素进行了考察,确定了微丸的包衣液的处方组成和包衣工艺。包衣液采用90%乙醇为溶剂,致孔剂(PEG6000)、抗粘剂(滑石粉)分别占包衣聚合物量的12%、20%。包衣增重为5%,老化时间为24小时。本文对所制缓释微丸的释药机制进行了探讨,结果表明所制微丸均符合一级动力学释药过程。采用相似因子法研究了缓释微丸的稳定性,结果表明缓释微丸在高温、高湿、光照试验条件下性质稳定。
采用高效液相色谱法,建立了家犬体内血药浓度的测定方法。以自制普通微丸胶囊作为参比制剂,研究了缓释微丸胶囊在家犬体内药代动力学。研究表明:缓释微丸胶囊在测定时间范围内血药浓度曲线与速释微丸相比,较为平稳,达峰时间有所延长,峰浓度下降。用非隔室模型统计矩法分析的参数也表明,缓释微丸中药物在体内的平均滞留时间延长,缓释效果较好,体内外相关性良好。
It is necessary to realize the modernization of Chinese traditional medicine to meet the request of the development of times. The modernization of preparation is the premise and base of the modernization of Chinese traditional medicine. In this paper, to adapt the need of clinic, Lysimachia clethroides Duby, the drug of anti-tumor, was selected as the model drug. On base of new method, new technology, new supplements and equipment, a new Chinese traditional medicinal sustained-release preparation was developed, which was accorded with the characteristics of Chinese traditional medicine. To assure the safety, therapeutic, efficiency, stability of the drug, strict quality standard was established, so the preparation could exert action and characteristics in preventing and curing diseases more efficiently.
Ultraviolet spectrophotometry method was developed for assaying during the study of content determination of the drug and release rate of the pellets. The method was accurate, liable, convenient and rapid, which meet the requirement of measurement. In the pre-formulation researches, the physicochemical properties of material drug were investigated, which were connected closely with pharmaceutic form design . The solubility of the drug in different buffer were increased while the apparent oil-water partition coefficient (Papp) decreased with the increase of pH value .In addition, the extract was stable when exposed to light,high temperature.
Extract total flavone from Lysimachia clethroides Duby through ethanol solution. Based on the studies of the influence factors,orthogonal test was used to optimize the extract conditions. The optimized extraction technics was to use 80% alcohol, 3times, 12 quantity and 2 hour per time. Then Three kinds of macro porous adsorbents were used to study adsorption performance for total flavone. The result showed that AB-8 was a kind of good adsorption resin for total flavone. In addition, the optimum conditions were filtered as follows: concentration of total flavone of liquid samples was 10 mg/mL, pH was 5.07, and fluid velocity was 1.0 mL/min, eluted by 40% alcohol at flow speed of 1.5 mL/min, total flavone in ZE4 reached 25.5%.
The absorption sites and the absorption kinetics were studied from various intestinal segments ligation using in situ perfusion method in rats. The research demonstrated that rutin was absorbed in the varied intestinal segments and mostly absorbed in jejunum .The mechanism of the gastrointestinal absorption of rutin was passive diffusion.
The process included the preparation of prompt-release pellets and coating of the pellets. HPC as dilute agent and water as adhesive agent ,the prompt-release pellets were prepared by the method of extrusion-spheronization. A fluid bed spray processor was adopted for coating the pellets. Using EC as coating material, the thesis screened the coating process parameters. The coating process variables were determined and controlled . The pellets was produced by with 90% alcohol and by filtration of a series of poreforming agent PEG6000( 12%), talc( 20%) , coating level( 5%) and curing time(24h).The description of dissolution profiles suggested that among the kinetics, the first-order became the most appropriate model to describe. The stability of the coated pellets was monitored. The results showed the coated pellets were stable under high temperature, high humidity, strong light.
Choosing rutin as standard sample, HPLC with UV detection was applied to analysis the plasma sample in dogs. The methods are accurate, liable, convenient and rapid, which meet the requirement of measurement.Pharmacokinetic studies of sustained-release and prompt-release capsule in dogs were performed based on determination of plasma concentration of drugs. The results showed, compared with prompt-release capsule, plasma concentration of sustained-release capsule was relatively stable, Tmax was postponed and Cmax was lowered and the mean residence time (MRT) was prolonged.The correlation study showed that a good relationship between in vivo and in vitro was built.
引文
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[3] 张景勍,张志荣. 中药靶向给药系统的研究进展[J]. 中草药,2000,31(增刊):23-24
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[5] 杨志文,杨木华,夏侯国三氧化二砷免疫毫微球的制备及鉴定[J].中国药学杂志 2008(2) : 115-117
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[8] 陈大为,张彦青,邹艳霜,等. 灯盏花素缓释微丸制备工艺与处方优化的研究[J]. 中草药, 2003, 34 (11) : 990
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[2] 王波.中药制剂现代化的探讨[J].中药材,2002,25(9):671-674
[3] 张景勍,张志荣. 中药靶向给药系统的研究进展[J]. 中草药,2000,31(增刊):23-24
[4] 刘晓华,杜文清,邵礼铮.抗癌中药复合 5-Fu 磁性微球制剂研制[J],中成药 1998(6) 4-7
[5] 杨志文,杨木华,夏侯国三氧化二砷免疫毫微球的制备及鉴定[J].中国药学杂志 2008(2) : 115-117
[6] 李药兰, 黄才欢.茶多酚缓释微囊的制备研究[J], 中药材, 2000,23(5) :2811
[7] 方 芳,张应辉,袁海龙,等. 毛冬青缓释胶囊的制备[J]. 解放军药学学报, 2004, 20 (6) : 470
[8] 陈大为,张彦青,邹艳霜,等. 灯盏花素缓释微丸制备工艺与处方优化的研究[J]. 中草药, 2003, 34 (11) : 990
[9] 中华本草编写组.中华本草[M].上海科技出版社. 1999;1(6):96-98
[10] 江苏新医学院. 中药大辞典[M].上海:上海人民卫生出版社,1977,1498
[11] Yasukawa K, Takido M. Studies on the chemical constituents of genus Lysmachia I. On the whole parts of Lysimachia japonica thumb and Lysimachia clethroides Duby[J]. Yakugaku Zasshi. 1986, 106(10): 939-941
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