银杏叶提取物速释滴丸的设计与评价
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摘要
银杏叶提取物(Extract of Ginkgo biloba，以下简称EGb)作为中药有效提取部位，广泛用于心脑血管疾病的治疗和预防，具有疗效好、副作用小等特点。为了进一步加快起效时间，并制成适合大工业生产的新剂型，本文以聚乙二醇6000(PEG6000)为载体材料，设计和研制了银杏叶提取物速释滴丸，并采用体内外不同方法对其进行了科学的评价。
经紫外扫描确定最大吸收波长为266nm，用于EGb在不同介质溶液中的稳定性考察和制剂在不同介质中的溶出性能对比考察；络合-比色分光光度法用于制剂处方筛选和含量测定中银杏总黄酮的定量分析，并结合双波长消去法用于测定大鼠在体银杏总黄酮肠吸收的情况；以槲皮素为标准品，EGb经酸水解后，进行高效液相法测定，计算银杏总黄酮的含量，但该法相对烦琐，仅运用于EGb制剂处方前相关性质的研究和制剂的质量评价；以芦丁为标准品，将血浆样品沉淀蛋白，经酸水解及进一步处理后，进行高效液相法测定，以此为指标进行制剂的体内评价。上述方法准确、可靠、方便、快捷，方法学考察指标均满足测定要求。
在制剂处方研究前，对与口服固体制剂设计密切相关的原料药理化性质进行了考察。EGb在H_2O，0.1mol／LHCl和pH6.8PBS中24h内吸光度无明显变化，稳定性较好；测定了EGb在H_2O，0.1mol／LHCl和pH6.8PBS中的平衡溶解度；不同pH下正辛醇／水系统中，银杏总黄酮的油水分配系数P_(app)值随着pH增大而减小，在pH3.0左右发生突变；EGb的软化至全熔温度为153.5～191.6℃；吸湿平衡实验测得EGb的临界相对湿度(CRH)约为80％；原料药的稳定性影响因素实验表明，在露置空气、光照、高湿及40℃条件下，EGb中银杏总黄酮的含量无明显变化，在60℃条件下含量有所降低；粉体学性质测试表明，EGb粉体流动性较差，具有喷流性。
采用大鼠在体回流实验方法研究了EGb在肠道的吸收情况。不同浓度
沈阳药科大学硕士学位论文 中文摘要
EGb大鼠全肠段吸收速率常数（KaX吸收量和吸收百分率测定结果表明，Ka
值和吸收百分率无明显差异，吸收量和药物浓度之间具有良好相关性，初
步推测吸收方式为被动扩散；在大鼠不同肠段十二指肠、空肠、回肠吸收
吸收情况表明，EGb在小肠上部吸收较好，尤以十二指肠段吸收最佳。
采用熔融法将EGb分散于辅料中，滴入冷凝液中收缩成丸。以滴丸粒
径、圆整度、丸重、溶出快慢为指标，经过单因素试验确定载药量及辅料
用量的大致范围。在此试验结果基础上，以溶出T扣为评价指标，运用三因
素正交试验设计筛选处方，确定其最佳用量；并结合实际条件，以丸重差
异为评价指标，选用三因素三水平正交设计筛选摘丸的滴制条件。三批样品
的重现性试验及稳定性加速试验结果表明，制备的EGb速释滴丸处方稳定、
质量可控，达到制剂的设计目的与要求。
速释机理考察部分中，测定EGb－PEG6000固体分散体和物理混合物的
熔点绘制相图，并进行DSC分析，推测固体分散体中EGb与PEG6000发
生某种形式的结合形成复合物；测定EGb在不同浓度PEG6000水溶液中的
溶解度，并考察不同比例E伽PEG6000固体分散体中E皿和PEG6000的
溶出性能，结合溶出模型理论，推测EGb在低载药量时，溶出模型属于载
体控制溶出型；EGb在高载药量时，溶出模型属于药物控制溶出型。
家犬药动学研究结果表明，自制银杏叶速释滴丸达到设计要求。自制
银杏叶滴丸药动学参数a较参比银杏叶片提前约1．3h。自制滴丸的相对生
物利用度为102．98％，隔室模型拟合体内药动学特征符合双隔室一级吸收过
程。
Extract from the leaves of Ginkgo biloba., as the effective part of herb, is widely used for treatment and prevention of cardiovascular and cerebrovascular diseases, which has the advantage of good therapy and little side-effect. To act further quickly and be suitable to industrial production, a fast release droppill was designed and prepared with polyethylene glycol 6000(PEG6000).
Firstly, UV spectrophotometry was developed for the stability and dissolution experiments of EGb or EGb preparation in different pH solution; complexing-colorimetry spectrophtometry was developed for determining the flavone glycosides of EGb in order to select formulations and measure intestinal absorption. Choosing Rutin and Quercetin as standard sample respectively, HPLC with UV detection was applied to evaluate stability and quality of EGb or EGb preparation and to analysis the plasma sample in dogs. The methods above are accurate, liable, convenient and rapid, which all reach the requirement of measurement.
In the preformulation researches, the physicochemical properties of EGb were investigated, which were connected closely with pharmaceutic form design. The result that the absorption of EGb by UV in distilled water, 0.1mol/L HC1 and pH6.8 phosphate buffer appeared no change showed better stability of EGb in these mediums and the study on solubility showed that the equilibrium solubility in the above three kinds of mediums were 0.30, 0.22, 0.30g/mL, respectively. The apparent oil-water partition coefficient(Papp) decreased with the increase of pH value in different pH n-octanol/water systems and changed violently about pH3.0. The melting range of EGb was 153.5-191.6 C; the critical relative humidity(CRH) was about 80%. In addition, the chemical stability of EGb was observed and the result indicated that exposure to air, light, humidity and temperature 40 C had little effect on it, but under temperature 60 C, the content of the flavone glycosides in EGb reduced. The determination of
powder properties showed that the EGb powder had bad fluidness.
To clarify the absorption of EGb from gastrointestine, the absorption rate constant, the absorption amount and the absorption percentage were measured by utilizing the rat intestinal recirculating method in situ. The result suggested that the mechanism of the rat intestinal absorption of EGb was via passive diffusion method by investigating absorption in lumen solutions with different concentrations. The experiment in different intestinal parts including duodenum, jejunum and ileum found that the absorption in the utter intestine was better, and best in the duodenum.
Droppills were prepared in this process: disperse EGb into the excipients by melting and drip the molten suspension into the condensation fluid, then drops were contracted, cooled and solidified into droppills. By the criterion of particle size, droppill weight, degree of circularity and dissolution rate, the amounts range of EGb and excipients were obtained through single factor experiment. The formulation was optimized on the basis of three factors and three levels orthogonal design by evaluating time of dissoluting 50 percent(T50) and the dripping condition was optimized using the same design by assessing mean variance of weigh. EGb droppills were prepared according to the best components and dripping condition. The repeatability of three batch samples and stability of accelerating test showed that fast release EGb droppills were stable, quality-controlled and met the purpose and requirement of dosage form design.
In the study of fast release mechanism, EGb-PEG6000 solid dispersion and physical mixture were analyzed by phase diagrams drew through measuring melting point and DSC method. Both analytical methods suggested that EGb and PEG6000 interact in molten state to form some kind of complex. Solubility of EGb in different concentrations of PEG6000 aqueous solution and dissolution rate of dispersions which had a range of EGb concentrations were investigated. Related to dissolution models, the result was spec
经紫外扫描确定最大吸收波长为266nm，用于EGb在不同介质溶液中的稳定性考察和制剂在不同介质中的溶出性能对比考察；络合-比色分光光度法用于制剂处方筛选和含量测定中银杏总黄酮的定量分析，并结合双波长消去法用于测定大鼠在体银杏总黄酮肠吸收的情况；以槲皮素为标准品，EGb经酸水解后，进行高效液相法测定，计算银杏总黄酮的含量，但该法相对烦琐，仅运用于EGb制剂处方前相关性质的研究和制剂的质量评价；以芦丁为标准品，将血浆样品沉淀蛋白，经酸水解及进一步处理后，进行高效液相法测定，以此为指标进行制剂的体内评价。上述方法准确、可靠、方便、快捷，方法学考察指标均满足测定要求。
在制剂处方研究前，对与口服固体制剂设计密切相关的原料药理化性质进行了考察。EGb在H_2O，0.1mol／LHCl和pH6.8PBS中24h内吸光度无明显变化，稳定性较好；测定了EGb在H_2O，0.1mol／LHCl和pH6.8PBS中的平衡溶解度；不同pH下正辛醇／水系统中，银杏总黄酮的油水分配系数P_(app)值随着pH增大而减小，在pH3.0左右发生突变；EGb的软化至全熔温度为153.5～191.6℃；吸湿平衡实验测得EGb的临界相对湿度(CRH)约为80％；原料药的稳定性影响因素实验表明，在露置空气、光照、高湿及40℃条件下，EGb中银杏总黄酮的含量无明显变化，在60℃条件下含量有所降低；粉体学性质测试表明，EGb粉体流动性较差，具有喷流性。
采用大鼠在体回流实验方法研究了EGb在肠道的吸收情况。不同浓度
沈阳药科大学硕士学位论文 中文摘要
EGb大鼠全肠段吸收速率常数（KaX吸收量和吸收百分率测定结果表明，Ka
值和吸收百分率无明显差异，吸收量和药物浓度之间具有良好相关性，初
步推测吸收方式为被动扩散；在大鼠不同肠段十二指肠、空肠、回肠吸收
吸收情况表明，EGb在小肠上部吸收较好，尤以十二指肠段吸收最佳。
采用熔融法将EGb分散于辅料中，滴入冷凝液中收缩成丸。以滴丸粒
径、圆整度、丸重、溶出快慢为指标，经过单因素试验确定载药量及辅料
用量的大致范围。在此试验结果基础上，以溶出T扣为评价指标，运用三因
素正交试验设计筛选处方，确定其最佳用量；并结合实际条件，以丸重差
异为评价指标，选用三因素三水平正交设计筛选摘丸的滴制条件。三批样品
的重现性试验及稳定性加速试验结果表明，制备的EGb速释滴丸处方稳定、
质量可控，达到制剂的设计目的与要求。
速释机理考察部分中，测定EGb－PEG6000固体分散体和物理混合物的
熔点绘制相图，并进行DSC分析，推测固体分散体中EGb与PEG6000发
生某种形式的结合形成复合物；测定EGb在不同浓度PEG6000水溶液中的
溶解度，并考察不同比例E伽PEG6000固体分散体中E皿和PEG6000的
溶出性能，结合溶出模型理论，推测EGb在低载药量时，溶出模型属于载
体控制溶出型；EGb在高载药量时，溶出模型属于药物控制溶出型。
家犬药动学研究结果表明，自制银杏叶速释滴丸达到设计要求。自制
银杏叶滴丸药动学参数a较参比银杏叶片提前约1．3h。自制滴丸的相对生
物利用度为102．98％，隔室模型拟合体内药动学特征符合双隔室一级吸收过
程。
Extract from the leaves of Ginkgo biloba., as the effective part of herb, is widely used for treatment and prevention of cardiovascular and cerebrovascular diseases, which has the advantage of good therapy and little side-effect. To act further quickly and be suitable to industrial production, a fast release droppill was designed and prepared with polyethylene glycol 6000(PEG6000).
Firstly, UV spectrophotometry was developed for the stability and dissolution experiments of EGb or EGb preparation in different pH solution; complexing-colorimetry spectrophtometry was developed for determining the flavone glycosides of EGb in order to select formulations and measure intestinal absorption. Choosing Rutin and Quercetin as standard sample respectively, HPLC with UV detection was applied to evaluate stability and quality of EGb or EGb preparation and to analysis the plasma sample in dogs. The methods above are accurate, liable, convenient and rapid, which all reach the requirement of measurement.
In the preformulation researches, the physicochemical properties of EGb were investigated, which were connected closely with pharmaceutic form design. The result that the absorption of EGb by UV in distilled water, 0.1mol/L HC1 and pH6.8 phosphate buffer appeared no change showed better stability of EGb in these mediums and the study on solubility showed that the equilibrium solubility in the above three kinds of mediums were 0.30, 0.22, 0.30g/mL, respectively. The apparent oil-water partition coefficient(Papp) decreased with the increase of pH value in different pH n-octanol/water systems and changed violently about pH3.0. The melting range of EGb was 153.5-191.6 C; the critical relative humidity(CRH) was about 80%. In addition, the chemical stability of EGb was observed and the result indicated that exposure to air, light, humidity and temperature 40 C had little effect on it, but under temperature 60 C, the content of the flavone glycosides in EGb reduced. The determination of
powder properties showed that the EGb powder had bad fluidness.
To clarify the absorption of EGb from gastrointestine, the absorption rate constant, the absorption amount and the absorption percentage were measured by utilizing the rat intestinal recirculating method in situ. The result suggested that the mechanism of the rat intestinal absorption of EGb was via passive diffusion method by investigating absorption in lumen solutions with different concentrations. The experiment in different intestinal parts including duodenum, jejunum and ileum found that the absorption in the utter intestine was better, and best in the duodenum.
Droppills were prepared in this process: disperse EGb into the excipients by melting and drip the molten suspension into the condensation fluid, then drops were contracted, cooled and solidified into droppills. By the criterion of particle size, droppill weight, degree of circularity and dissolution rate, the amounts range of EGb and excipients were obtained through single factor experiment. The formulation was optimized on the basis of three factors and three levels orthogonal design by evaluating time of dissoluting 50 percent(T50) and the dripping condition was optimized using the same design by assessing mean variance of weigh. EGb droppills were prepared according to the best components and dripping condition. The repeatability of three batch samples and stability of accelerating test showed that fast release EGb droppills were stable, quality-controlled and met the purpose and requirement of dosage form design.
In the study of fast release mechanism, EGb-PEG6000 solid dispersion and physical mixture were analyzed by phase diagrams drew through measuring melting point and DSC method. Both analytical methods suggested that EGb and PEG6000 interact in molten state to form some kind of complex. Solubility of EGb in different concentrations of PEG6000 aqueous solution and dissolution rate of dispersions which had a range of EGb concentrations were investigated. Related to dissolution models, the result was spec
引文
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