中药灯盏花素骨架缓释微丸的设计与评价
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摘要
灯盏花素是从菊科短葶飞蓬属植物灯盏细辛(Erigeron breviscapus)中提取出来的黄酮类有效成分，主要为灯盏花甲素和乙素的混合物，其中灯盏花乙素(Scutellarin)含量占95％以上。作为一种新型活血化瘀中药，灯盏花素具有疗效好、用途广、不良反应少等优点，在临床上主要用于治疗脑梗死、冠心病、心绞痛等。为了满足预防和治疗心脑血管性疾病长期用药的临床需求，达到减少服用次数、降低毒副作用、提高生物利用度的目的，并能适合工业化大生产的需要，本文以乙基纤维素和硬脂酸作为缓释材料，利用挤出-滚圆法制备了日服两次的灯盏花素疏水性骨架缓释微丸。
建立了紫外分光光度法用于灯盏花素的制剂含量、释放度及基本性质的测定；建立了紫外高效液相色谱法用于灯盏花素原料药和溶液稳定性的研究；采用双波长分光光度法测定肠循环液中灯盏花素的含量，研究大鼠在体肠吸收动力学。上述方法准确、可靠、方便、快捷，很好地满足了本研究中各项分析测试的要求。
对与制剂处方设计密切相关的灯盏花素的基本理化性质进行了考察。测定了灯盏花素在0.1mol／L HCl、水、pH6.8和pH7.4磷酸盐缓冲液中的平衡溶解度(37℃)，分别为1.45+0.03，31.5+0.8，7946.3±27.1，19045.1±257.9μg／ml；不同pH值下正辛醇／水系统中油／水分配系数(P_(app))测定结果表明，灯盏花素在酸性条件下P_(app)较大；原料药固体粉末的初步稳定性影响因素考察表明灯盏花素对光照、空气较稳定，但是在高温、高湿条件下含量略有降低；对灯盏花素溶液稳定性进行研究，结果发现温度、pH值对其稳定性有显著性影响，充氮或加入抗氧剂能明显减少灯盏花素的降解，其中对抗氧剂作用进行考察，结果表明EDTA-2Na在不同介质中对灯盏花素均有良好的稳定作用。
采用在体回流实验研究了灯盏花素在大鼠肠道的吸收情况。在体肠回
沈阳药科大学硕士学位论文 摘 要
流6卜后得到不同条件下的吸收速率常数，结果发现十二指肠、空肠、回肠
和结肠的吸收速率常数分别为 0．0486，0．0587，0．0756f［ 0．106h－，依次
增大并具显著性差异；pH值和胆管结扎对药物吸收无显著性影l响，但不同
浓度下的吸收速率常数有明显差异。在体肠吸收实验的结果证实可以通过
控制药物释放达到改善吸收的目的。
选择挤出－滚圆沧制备了以乙基纤维素和硬脂酸为疏水性材料的骨架
缓释微丸。在单因素考察的基础上，采用正交试验优化处方，筛选出体外
缓释达12h的最优处方，制成日服两次的缓释制剂；药物的释放动力学过
程较好地符合Peppas方程和 Higuchi方程，通过模型拟合和电镜扫描结果
确证灯盏花素缓释微丸的释药机理为以药物扩散为主兼有骨架溶蚀的
non－Flckian过程。
本文以血小板聚集抑制率作为药理效应指标，测定了灯盏花素的药效
动力学过程。结果发现灯盏花素对血小板抑制强度与剂量呈线性正相关，
该指标可用于灯盏花素药效动力学测定。选择市售普通片作参比制剂，利
用药理效应治测定健康家兔口服灯盏花素缓释微丸的时效曲线并计算药效
动力学参数和相对生物利用度。在测定时间范围内时效曲线较平稳，可维
持体内药效达12h左右，相对生物利用度为149．2％，统计分析结果显示与
参比制剂（市售普通片）为非生物等效制剂，自制缓释微丸的生物利用度
明显高于参比制剂。时效动力学研究结果表明灯盏花素缓释微丸达到了预
期设计的目的。
Breviscapin were the flavonoids extracted from the Erigeron breviscapus (Vant.) Hand.-Mazz. Breviscapin were mainly the mixture of 4'-hydroxy -7-O-p-D-Pyrangluconate methyl ester and scutellarin and the content of scutellarin was above 95 percent. As a new type of Chinese proprietary medicines breviscapin, which can promote blood circulation to remove blood stasis, showed characteristic of good curative effects, wide uses, less side-effects. Breviscapin is efficacious in the treatment of cerebral infarction, coronary heart disease, angina pectoris. To meet clinical need for long time use of drugs for prevent and treatment of cardiovascular disease and cerebrovascular disease, to attain the aim of reducing times of administration and side effects breviscapin sustained release pellets of twice daily administration were prepared using ethylcellulose (EC) and stearic acid (SA) as the basic sustained excipient. The pellets were prepared by extrusion -spheronization method.
Ultraviolet spectrophotometry method was developed for assaying during the study of physiochemical properties, content and drug release. High-performance liquid chromatography with UV detection was developed for studying the stability of breviscapin. In order to exclude the interference of the circulating solution and phenol red, dual-wavelength spectrophotometry was developed for in situ absorption.
The physicochemical properties of breviscapin were investigated, which were connected closely with pharmaceutic form design. The studies on solubility showed that the equilibrium solubility in distilled water, pH 6.8
phosphate buffer, pH 7.4 phosphate buffer were 1.45?.03,31.5?.8, 7946.3?7.1, 19045.1?57.9#g/ml respectively; Apparent oil-water partition coefficient in the system of n-octylalcohol and water was relatively higher in acid environment.
The chemical stability of solid breviscapin was observed, the result of which indicated that light and air had little effect on it , but content of scutellarin decreased slightly under high temperature and high humidity. The stability of breviscapin in solution was studied. Results demonstrated that temperature and pH Value had significant influence on its stability, inflating N2 and adding antioxidants could improve the stability of breviscapin. Functions of different antioxidants were investigated, results showed that EDTA-2Na had good function in different medium. To clarify the absorption of breviscapin from intestine, the absorption was studied by utilizing the rat intestinal absorption recirculating method in situ. After perfusing for 6 h, the permeability rate showed that the permeability rate constant (h-1) of deodenum, jejunum, ileum and colon per 10cm were 0.0486, 0.0587, 0.0756, 0.106h-1 increasing accordingly and having significant difference. The bile duct ligated and pH value had no significant influence on it, but significant difference was found between different concentrations.
The sustained release pellets were prepared with EC and SA by extrusion-spheronization method. Based on the studies of the influence factors, optimal formulation modified to release drug over 12h was obtained by orthogonal design test. The release profiles of sustained release pellets in vitro complied with Higuchi equation as well as Peppas equation. It suggested that the release of breviscapin could be described as non-Fickian diffusion, which was mainly by diffusion from pellets associated with slight erosion.
In this part, the pharmacodynamics of breviscapin was studied in the blood platelet inhibition rate as the pharmacological index. Results showed that the dose-response relationship was linear. This index could be used to study on the
pharmacodynamics of breviscapin. Effect-time profiles in healthy rabbits after oral administration of sustained release pellets and normal tablet were determined by pharmacological method and the pharmacodynamics parameters were calculated. The effect maintained for about 12h. The result of stastical analysis showed that breviscapin sustained relea
建立了紫外分光光度法用于灯盏花素的制剂含量、释放度及基本性质的测定；建立了紫外高效液相色谱法用于灯盏花素原料药和溶液稳定性的研究；采用双波长分光光度法测定肠循环液中灯盏花素的含量，研究大鼠在体肠吸收动力学。上述方法准确、可靠、方便、快捷，很好地满足了本研究中各项分析测试的要求。
对与制剂处方设计密切相关的灯盏花素的基本理化性质进行了考察。测定了灯盏花素在0.1mol／L HCl、水、pH6.8和pH7.4磷酸盐缓冲液中的平衡溶解度(37℃)，分别为1.45+0.03，31.5+0.8，7946.3±27.1，19045.1±257.9μg／ml；不同pH值下正辛醇／水系统中油／水分配系数(P_(app))测定结果表明，灯盏花素在酸性条件下P_(app)较大；原料药固体粉末的初步稳定性影响因素考察表明灯盏花素对光照、空气较稳定，但是在高温、高湿条件下含量略有降低；对灯盏花素溶液稳定性进行研究，结果发现温度、pH值对其稳定性有显著性影响，充氮或加入抗氧剂能明显减少灯盏花素的降解，其中对抗氧剂作用进行考察，结果表明EDTA-2Na在不同介质中对灯盏花素均有良好的稳定作用。
采用在体回流实验研究了灯盏花素在大鼠肠道的吸收情况。在体肠回
沈阳药科大学硕士学位论文 摘 要
流6卜后得到不同条件下的吸收速率常数，结果发现十二指肠、空肠、回肠
和结肠的吸收速率常数分别为 0．0486，0．0587，0．0756f［ 0．106h－，依次
增大并具显著性差异；pH值和胆管结扎对药物吸收无显著性影l响，但不同
浓度下的吸收速率常数有明显差异。在体肠吸收实验的结果证实可以通过
控制药物释放达到改善吸收的目的。
选择挤出－滚圆沧制备了以乙基纤维素和硬脂酸为疏水性材料的骨架
缓释微丸。在单因素考察的基础上，采用正交试验优化处方，筛选出体外
缓释达12h的最优处方，制成日服两次的缓释制剂；药物的释放动力学过
程较好地符合Peppas方程和 Higuchi方程，通过模型拟合和电镜扫描结果
确证灯盏花素缓释微丸的释药机理为以药物扩散为主兼有骨架溶蚀的
non－Flckian过程。
本文以血小板聚集抑制率作为药理效应指标，测定了灯盏花素的药效
动力学过程。结果发现灯盏花素对血小板抑制强度与剂量呈线性正相关，
该指标可用于灯盏花素药效动力学测定。选择市售普通片作参比制剂，利
用药理效应治测定健康家兔口服灯盏花素缓释微丸的时效曲线并计算药效
动力学参数和相对生物利用度。在测定时间范围内时效曲线较平稳，可维
持体内药效达12h左右，相对生物利用度为149．2％，统计分析结果显示与
参比制剂（市售普通片）为非生物等效制剂，自制缓释微丸的生物利用度
明显高于参比制剂。时效动力学研究结果表明灯盏花素缓释微丸达到了预
期设计的目的。
Breviscapin were the flavonoids extracted from the Erigeron breviscapus (Vant.) Hand.-Mazz. Breviscapin were mainly the mixture of 4'-hydroxy -7-O-p-D-Pyrangluconate methyl ester and scutellarin and the content of scutellarin was above 95 percent. As a new type of Chinese proprietary medicines breviscapin, which can promote blood circulation to remove blood stasis, showed characteristic of good curative effects, wide uses, less side-effects. Breviscapin is efficacious in the treatment of cerebral infarction, coronary heart disease, angina pectoris. To meet clinical need for long time use of drugs for prevent and treatment of cardiovascular disease and cerebrovascular disease, to attain the aim of reducing times of administration and side effects breviscapin sustained release pellets of twice daily administration were prepared using ethylcellulose (EC) and stearic acid (SA) as the basic sustained excipient. The pellets were prepared by extrusion -spheronization method.
Ultraviolet spectrophotometry method was developed for assaying during the study of physiochemical properties, content and drug release. High-performance liquid chromatography with UV detection was developed for studying the stability of breviscapin. In order to exclude the interference of the circulating solution and phenol red, dual-wavelength spectrophotometry was developed for in situ absorption.
The physicochemical properties of breviscapin were investigated, which were connected closely with pharmaceutic form design. The studies on solubility showed that the equilibrium solubility in distilled water, pH 6.8
phosphate buffer, pH 7.4 phosphate buffer were 1.45?.03,31.5?.8, 7946.3?7.1, 19045.1?57.9#g/ml respectively; Apparent oil-water partition coefficient in the system of n-octylalcohol and water was relatively higher in acid environment.
The chemical stability of solid breviscapin was observed, the result of which indicated that light and air had little effect on it , but content of scutellarin decreased slightly under high temperature and high humidity. The stability of breviscapin in solution was studied. Results demonstrated that temperature and pH Value had significant influence on its stability, inflating N2 and adding antioxidants could improve the stability of breviscapin. Functions of different antioxidants were investigated, results showed that EDTA-2Na had good function in different medium. To clarify the absorption of breviscapin from intestine, the absorption was studied by utilizing the rat intestinal absorption recirculating method in situ. After perfusing for 6 h, the permeability rate showed that the permeability rate constant (h-1) of deodenum, jejunum, ileum and colon per 10cm were 0.0486, 0.0587, 0.0756, 0.106h-1 increasing accordingly and having significant difference. The bile duct ligated and pH value had no significant influence on it, but significant difference was found between different concentrations.
The sustained release pellets were prepared with EC and SA by extrusion-spheronization method. Based on the studies of the influence factors, optimal formulation modified to release drug over 12h was obtained by orthogonal design test. The release profiles of sustained release pellets in vitro complied with Higuchi equation as well as Peppas equation. It suggested that the release of breviscapin could be described as non-Fickian diffusion, which was mainly by diffusion from pellets associated with slight erosion.
In this part, the pharmacodynamics of breviscapin was studied in the blood platelet inhibition rate as the pharmacological index. Results showed that the dose-response relationship was linear. This index could be used to study on the
pharmacodynamics of breviscapin. Effect-time profiles in healthy rabbits after oral administration of sustained release pellets and normal tablet were determined by pharmacological method and the pharmacodynamics parameters were calculated. The effect maintained for about 12h. The result of stastical analysis showed that breviscapin sustained relea
引文
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