藏药小檗皮提取物的成药性研究
发布时间：2018-09-19 11:27
【摘要】：糖尿病及其并发症属于重大疑难疾病,目前尚未证实有确切治疗糖尿病视网膜病变的药物,因此早期防治是关键。“京尼萨库病(糖尿病)”是藏医药防治的特色优势病种,糖尿病专科被列入国家中医药管理局十一五建设的重点专科。藏药小檗皮为藏医临床治疗糖尿病及其并发症(包括糖尿病视网膜病变等糖尿病性微血管病变并发症)的常用药物,《月王药诊》《医学四续》《晶珠本草》等藏医药经典古籍皆有藏药小檗皮防治“京尼萨库病(糖尿病)”的相关记载,并被收载于《中华人民共和国卫生部药品标准·藏药(第一册)》等标准中。前期研究发现,藏药小檗皮不仅能够明显降低糖尿病视网膜病变模型鼠的血糖水平,并且对其视网膜血管损伤具有明显改善作用。藏医临床常用小檗中皮熬膏治疗“京尼萨库”眼病,课题组以总生物碱含量和浸膏收得率为考察指标,对藏药小檗皮的传统水煎煮提取工艺参数进行了优化,为藏医临床应用提供工艺稳定、质量可控的小檗膏。为了发挥藏医药防治“京尼萨库病(糖尿病)”的临床优势与特色,有必要对藏药小檗皮提取物的成药性进行试验研究。目的1.分析药理学试验数据与化学成分分析数据的相关性,明确藏药小檗皮提取物Ⅰ(根据藏医临床用法制成的小檗膏)有效部位及成药性研究必要性；2.测定盐酸小檗胺单一制剂的溶出度,推测相关成分在体内的吸收利用情况；3.建立藏药小檗皮提取物Ⅰ中3种生物碱含量的高效液相色谱法测定方法,为藏药小檗皮提取物Ⅰ质量控制提供依据；4.筛选藏药小檗皮提取物Ⅱ(总生物碱有效部位)的纯化工艺,为后期剂型研究提供原料。方法1.对前期课题组研究所得的藏药小檗皮提取物Ⅰ(根据藏医临床用法制成的小檗膏)与糖尿病视网膜病变相关的药理学试验数据(研究数据已公开发表)与化学成分分析结果进行相关性分析；2.盐酸小檗胺为藏药小檗皮及藏药小檗皮提取物Ⅰ的有效成分之一,其单一制剂为盐酸小檗胺片,测定市售盐酸小檗胺片的溶出度,预测盐酸小檗胺等生物碱成分在体内的吸收情况；3.建立藏药小檗皮提取物Ⅰ中有效成分盐酸药根碱、盐酸巴马汀、盐酸小檗碱3种生物碱含量的高效液相色谱测定方法；4.筛选藏药小檗皮提取物Ⅰ中总生物碱有效部位(藏药小檗皮提取物Ⅱ)的大孔吸附树脂法纯化工艺参数,为藏药小檗皮提取物的后续研究与开发提供基础。结果1.相关性分析结果表明藏药小檗皮提取物Ⅰ及其主要生物碱成分具有防治糖尿病视网膜病变的应用前景,其防治机理可能与阻断糖尿病视网膜病变血管通透性的恶性循环有关,为藏医临床应用小檗皮防治糖尿病及其并发症糖尿病视网膜病变提供科学依据,并进一步解释了藏医临床口服治疗糖尿病及其并发症糖尿病视网膜病变的有效作用机制,验证了藏药小檗皮提取物(根据藏医临床用法制备而成)及其主要生物碱成分对糖尿病视网膜病变的有效作用；2.溶出度试验结果发现各个批次的市售盐酸小檗胺片在人工肠液中的溶出度均高于人工胃液,预测盐酸小檗胺可能在肠道部位的吸收较好,推测肠道是藏药小檗皮提取物口服制剂剂型的主要吸收部位；3.建立了藏药小檗皮提取物Ⅰ中盐酸药根碱碱、盐酸巴马汀、盐酸小檗碱3种主要生物碱的高效液相色谱法测定方法,3种生物碱浓度分别在4.3886-87.7716(r=0.9997).3.6649～73.2982(r=0.9998).29.5994～591.9876(r=0.9999) μg·mL~(-1)范围内线性关系良好(n=8)；平均加样回收率(n=9)分别为97.97%(RSD=1.02%)、100.70%(RSD=1.42%)、98.51%(RSD=0.86%),建立的3.种生物碱含量方法准确度与重复性良好,可作为藏药小檗膏提取物的质量控制方法。4.筛选出大孔吸附树脂纯化工艺的最佳工艺参数为：采用HPD100型大孔吸附树脂,上样液总生物碱浓度为3 mg.mL~(-1),上样速度为1 mL·min-1,用4 BV的纯化水洗脱除去水溶性杂质,再用7 BV30%乙醇溶液以2 mL·min-1的流速洗脱,收集流出液,浓缩、干燥成为粉末,即为藏药小檗皮提取物Ⅰ的总生物碱有效部位(藏药小檗皮提取物Ⅱ),以总生物碱计算,以紫外分光光度法和高效液相色谱法两种测定方法含量均高于50%,为后期进一步的剂型选择、质量控制、临床试验等研究与开发提供基础。结论藏药小檗皮中以小檗碱为代表的生物碱类成分对糖尿病视网膜病变具有良好的防治作用,预测该类成分可能在肠道部位吸收较好,本实验制备所得藏药小檗皮提取物Ⅱ可作为后续防治糖尿病视网膜病变口服肠溶固体制剂原料。
[Abstract]:Diabetes mellitus and its complications are major and difficult diseases, and there are no definite drugs to treat diabetic retinopathy, so early prevention and treatment is the key. Berberis is a common Tibetan medicine for the treatment of diabetes and its complications (including diabetic retinopathy and other diabetic microangiopathy complications). The classical Tibetan medicine books such as < Yue Wang Yao Dian > < Medicines Fourth Sequel > < Jing Zhu Materia Medica > all contain the relevant records of the Tibetan medicine Berberis for the prevention and treatment of "Jingnisaku disease (diabetes)". Previous studies have found that Berberis bark can not only significantly reduce the blood sugar level of diabetic retinopathy model rats, but also significantly improve the retinal vascular injury. Berberis bark plaster is commonly used in Tibetan medicine clinical treatment of "Jingnisa" In order to give full play to the clinical advantages and characteristics of Tibetan medicine in the prevention and treatment of Jingnisaku disease (diabetes mellitus), the research group optimized the traditional decocting and extracting process parameters of Berberis bark. OBJECTIVE 1. To analyze the correlation between pharmacological test data and chemical composition analysis data, to clarify the effective parts of Berberis bark extract I (Berberis ointment made according to the clinical usage of Tibetan medicine) and the necessity of its medicinal preparation; 2. To determine the dissolution of berbamine hydrochloride in a single preparation. 3. To establish a high performance liquid chromatographic method for the determination of three alkaloids in Berberis Berberis Extract I, and to provide a basis for the quality control of Berberis Berberis Extract I. 4. To screen the purification process of Berberis Berberis Extract II (the effective part of total alkaloids) for the later preparation. METHODS 1. Correlation analysis was made between pharmacological test data (published data) and chemical composition analysis results of Berberine Hydrochloride extract I (Berberine Hydrochloride) from Tibetan medicine, which was prepared by Tibetan medicine clinical method, and related to diabetic retinopathy. 2. Berberine Hydrochloride was used as Tibetan medicine. Berberine hydrochloride tablet is one of the effective components of Berberis bark extract I. The dissolution of commercial berbamine hydrochloride tablets was determined to predict the absorption of berbamine hydrochloride and other alkaloids in vivo. 3. The effective components of Berberine hydrochloride extract I were established. High performance liquid chromatographic method for the determination of three alkaloids in Berberis bark extract; 4. Screening the purification process parameters of effective fraction of total alkaloids in Berberis bark extract I (Berberis bark extract II) by macroporous adsorption resin, providing a basis for the follow-up research and development of Berberis bark extract. Results 1. Correlation analysis showed that the Tibetan Berberis effective. Berberis bark extract I and its main alkaloids have potential applications in the prevention and treatment of diabetic retinopathy. The mechanism of prevention and treatment may be related to blocking the vascular permeability of diabetic retinopathy and malignant circulation. It provides scientific basis for the clinical application of Berberis bark in Tibetan medicine in the prevention and treatment of diabetic retinopathy and its complications. The effective mechanism of Tibetan medicine oral treatment of diabetes mellitus and its complications diabetic retinopathy was further explained, and the effective effect of Tibetan medicine Berberis extract (prepared according to the clinical preparation of Tibetan medicine) and its main alkaloids on diabetic retinopathy was verified. 2. Dissolution test results found that each batch of the test. The dissolution of berbamine hydrochloride tablets in artificial intestinal juice was higher than that in artificial gastric juice. It was predicted that the absorption of berbamine hydrochloride in intestinal tract was better. It was speculated that intestinal tract was the main absorption part of oral preparation of Berberis extract from Tibetan medicine. 3. The three main alkaloids of berberine were determined by high performance liquid chromatography. The concentration of the three alkaloids ranged from 4.3886-87.7716 (r=0.9997). 3.6649-73.2982 (r=0.9998). 29.5994-591.9876 (r=0.9999) ug.mL-1) with good linear relationship (n=8), and the average recovery (n=9) were 97.97% (RSD=1.02%) and 100.70% (RSD=1.42%) respectively. 51% (RSD = 0.86%). The three alkaloids content methods established were accurate and reproducible, and could be used as the quality control method for extracts of Berberis extract. 4. The optimum process parameters of macroporous adsorption resin purification were screened out as follows: HPD 100 macroporous adsorption resin, total alkaloids concentration of sample solution was 3 mg. mL~(-1), sample loading rate was 1 mL (-1). The effluent was collected, concentrated and dried to powder. The effluent was the total alkaloid effective fraction of Berberis bark extract I (Berberis bark extract II), calculated by total alkaloids, and determined by ultraviolet spectrophotometry and high efficiency solution. The contents of the two methods were higher than 50%, which provided the basis for the further study and development of dosage form selection, quality control and clinical trial in the later period. The extract II from Berberis bark can be used as a solid enteric-coated preparation for the follow-up prevention and treatment of diabetic retinopathy.
【学位授予单位】：成都中医药大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R29
[Abstract]:Diabetes mellitus and its complications are major and difficult diseases, and there are no definite drugs to treat diabetic retinopathy, so early prevention and treatment is the key. Berberis is a common Tibetan medicine for the treatment of diabetes and its complications (including diabetic retinopathy and other diabetic microangiopathy complications). The classical Tibetan medicine books such as < Yue Wang Yao Dian > < Medicines Fourth Sequel > < Jing Zhu Materia Medica > all contain the relevant records of the Tibetan medicine Berberis for the prevention and treatment of "Jingnisaku disease (diabetes)". Previous studies have found that Berberis bark can not only significantly reduce the blood sugar level of diabetic retinopathy model rats, but also significantly improve the retinal vascular injury. Berberis bark plaster is commonly used in Tibetan medicine clinical treatment of "Jingnisa" In order to give full play to the clinical advantages and characteristics of Tibetan medicine in the prevention and treatment of Jingnisaku disease (diabetes mellitus), the research group optimized the traditional decocting and extracting process parameters of Berberis bark. OBJECTIVE 1. To analyze the correlation between pharmacological test data and chemical composition analysis data, to clarify the effective parts of Berberis bark extract I (Berberis ointment made according to the clinical usage of Tibetan medicine) and the necessity of its medicinal preparation; 2. To determine the dissolution of berbamine hydrochloride in a single preparation. 3. To establish a high performance liquid chromatographic method for the determination of three alkaloids in Berberis Berberis Extract I, and to provide a basis for the quality control of Berberis Berberis Extract I. 4. To screen the purification process of Berberis Berberis Extract II (the effective part of total alkaloids) for the later preparation. METHODS 1. Correlation analysis was made between pharmacological test data (published data) and chemical composition analysis results of Berberine Hydrochloride extract I (Berberine Hydrochloride) from Tibetan medicine, which was prepared by Tibetan medicine clinical method, and related to diabetic retinopathy. 2. Berberine Hydrochloride was used as Tibetan medicine. Berberine hydrochloride tablet is one of the effective components of Berberis bark extract I. The dissolution of commercial berbamine hydrochloride tablets was determined to predict the absorption of berbamine hydrochloride and other alkaloids in vivo. 3. The effective components of Berberine hydrochloride extract I were established. High performance liquid chromatographic method for the determination of three alkaloids in Berberis bark extract; 4. Screening the purification process parameters of effective fraction of total alkaloids in Berberis bark extract I (Berberis bark extract II) by macroporous adsorption resin, providing a basis for the follow-up research and development of Berberis bark extract. Results 1. Correlation analysis showed that the Tibetan Berberis effective. Berberis bark extract I and its main alkaloids have potential applications in the prevention and treatment of diabetic retinopathy. The mechanism of prevention and treatment may be related to blocking the vascular permeability of diabetic retinopathy and malignant circulation. It provides scientific basis for the clinical application of Berberis bark in Tibetan medicine in the prevention and treatment of diabetic retinopathy and its complications. The effective mechanism of Tibetan medicine oral treatment of diabetes mellitus and its complications diabetic retinopathy was further explained, and the effective effect of Tibetan medicine Berberis extract (prepared according to the clinical preparation of Tibetan medicine) and its main alkaloids on diabetic retinopathy was verified. 2. Dissolution test results found that each batch of the test. The dissolution of berbamine hydrochloride tablets in artificial intestinal juice was higher than that in artificial gastric juice. It was predicted that the absorption of berbamine hydrochloride in intestinal tract was better. It was speculated that intestinal tract was the main absorption part of oral preparation of Berberis extract from Tibetan medicine. 3. The three main alkaloids of berberine were determined by high performance liquid chromatography. The concentration of the three alkaloids ranged from 4.3886-87.7716 (r=0.9997). 3.6649-73.2982 (r=0.9998). 29.5994-591.9876 (r=0.9999) ug.mL-1) with good linear relationship (n=8), and the average recovery (n=9) were 97.97% (RSD=1.02%) and 100.70% (RSD=1.42%) respectively. 51% (RSD = 0.86%). The three alkaloids content methods established were accurate and reproducible, and could be used as the quality control method for extracts of Berberis extract. 4. The optimum process parameters of macroporous adsorption resin purification were screened out as follows: HPD 100 macroporous adsorption resin, total alkaloids concentration of sample solution was 3 mg. mL~(-1), sample loading rate was 1 mL (-1). The effluent was collected, concentrated and dried to powder. The effluent was the total alkaloid effective fraction of Berberis bark extract I (Berberis bark extract II), calculated by total alkaloids, and determined by ultraviolet spectrophotometry and high efficiency solution. The contents of the two methods were higher than 50%, which provided the basis for the further study and development of dosage form selection, quality control and clinical trial in the later period. The extract II from Berberis bark can be used as a solid enteric-coated preparation for the follow-up prevention and treatment of diabetic retinopathy.
【学位授予单位】：成都中医药大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R29
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