藏藥小檗皮提取物的成藥性研究
發(fā)布時(shí)間：2018-09-19 11:27
【摘要】：糖尿病及其并發(fā)癥屬于重大疑難疾病,目前尚未證實(shí)有確切治療糖尿病視網(wǎng)膜病變的藥物,因此早期防治是關(guān)鍵。“京尼薩庫(kù)病(糖尿病)”是藏醫(yī)藥防治的特色優(yōu)勢(shì)病種,糖尿病專(zhuān)科被列入國(guó)家中醫(yī)藥管理局十一五建設(shè)的重點(diǎn)專(zhuān)科。藏藥小檗皮為藏醫(yī)臨床治療糖尿病及其并發(fā)癥(包括糖尿病視網(wǎng)膜病變等糖尿病性微血管病變并發(fā)癥)的常用藥物,《月王藥診》《醫(yī)學(xué)四續(xù)》《晶珠本草》等藏醫(yī)藥經(jīng)典古籍皆有藏藥小檗皮防治“京尼薩庫(kù)病(糖尿病)”的相關(guān)記載,并被收載于《中華人民共和國(guó)衛(wèi)生部藥品標(biāo)準(zhǔn)·藏藥(第一冊(cè))》等標(biāo)準(zhǔn)中。前期研究發(fā)現(xiàn),藏藥小檗皮不僅能夠明顯降低糖尿病視網(wǎng)膜病變模型鼠的血糖水平,并且對(duì)其視網(wǎng)膜血管損傷具有明顯改善作用。藏醫(yī)臨床常用小檗中皮熬膏治療“京尼薩庫(kù)”眼病,課題組以總生物堿含量和浸膏收得率為考察指標(biāo),對(duì)藏藥小檗皮的傳統(tǒng)水煎煮提取工藝參數(shù)進(jìn)行了優(yōu)化,為藏醫(yī)臨床應(yīng)用提供工藝穩(wěn)定、質(zhì)量可控的小檗膏。為了發(fā)揮藏醫(yī)藥防治“京尼薩庫(kù)病(糖尿病)”的臨床優(yōu)勢(shì)與特色,有必要對(duì)藏藥小檗皮提取物的成藥性進(jìn)行試驗(yàn)研究。目的1.分析藥理學(xué)試驗(yàn)數(shù)據(jù)與化學(xué)成分分析數(shù)據(jù)的相關(guān)性,明確藏藥小檗皮提取物Ⅰ(根據(jù)藏醫(yī)臨床用法制成的小檗膏)有效部位及成藥性研究必要性；2.測(cè)定鹽酸小檗胺單一制劑的溶出度,推測(cè)相關(guān)成分在體內(nèi)的吸收利用情況；3.建立藏藥小檗皮提取物Ⅰ中3種生物堿含量的高效液相色譜法測(cè)定方法,為藏藥小檗皮提取物Ⅰ質(zhì)量控制提供依據(jù)；4.篩選藏藥小檗皮提取物Ⅱ(總生物堿有效部位)的純化工藝,為后期劑型研究提供原料。方法1.對(duì)前期課題組研究所得的藏藥小檗皮提取物Ⅰ(根據(jù)藏醫(yī)臨床用法制成的小檗膏)與糖尿病視網(wǎng)膜病變相關(guān)的藥理學(xué)試驗(yàn)數(shù)據(jù)(研究數(shù)據(jù)已公開(kāi)發(fā)表)與化學(xué)成分分析結(jié)果進(jìn)行相關(guān)性分析；2.鹽酸小檗胺為藏藥小檗皮及藏藥小檗皮提取物Ⅰ的有效成分之一,其單一制劑為鹽酸小檗胺片,測(cè)定市售鹽酸小檗胺片的溶出度,預(yù)測(cè)鹽酸小檗胺等生物堿成分在體內(nèi)的吸收情況；3.建立藏藥小檗皮提取物Ⅰ中有效成分鹽酸藥根堿、鹽酸巴馬汀、鹽酸小檗堿3種生物堿含量的高效液相色譜測(cè)定方法；4.篩選藏藥小檗皮提取物Ⅰ中總生物堿有效部位(藏藥小檗皮提取物Ⅱ)的大孔吸附樹(shù)脂法純化工藝參數(shù),為藏藥小檗皮提取物的后續(xù)研究與開(kāi)發(fā)提供基礎(chǔ)。結(jié)果1.相關(guān)性分析結(jié)果表明藏藥小檗皮提取物Ⅰ及其主要生物堿成分具有防治糖尿病視網(wǎng)膜病變的應(yīng)用前景,其防治機(jī)理可能與阻斷糖尿病視網(wǎng)膜病變血管通透性的惡性循環(huán)有關(guān),為藏醫(yī)臨床應(yīng)用小檗皮防治糖尿病及其并發(fā)癥糖尿病視網(wǎng)膜病變提供科學(xué)依據(jù),并進(jìn)一步解釋了藏醫(yī)臨床口服治療糖尿病及其并發(fā)癥糖尿病視網(wǎng)膜病變的有效作用機(jī)制,驗(yàn)證了藏藥小檗皮提取物(根據(jù)藏醫(yī)臨床用法制備而成)及其主要生物堿成分對(duì)糖尿病視網(wǎng)膜病變的有效作用；2.溶出度試驗(yàn)結(jié)果發(fā)現(xiàn)各個(gè)批次的市售鹽酸小檗胺片在人工腸液中的溶出度均高于人工胃液,預(yù)測(cè)鹽酸小檗胺可能在腸道部位的吸收較好,推測(cè)腸道是藏藥小檗皮提取物口服制劑劑型的主要吸收部位；3.建立了藏藥小檗皮提取物Ⅰ中鹽酸藥根堿堿、鹽酸巴馬汀、鹽酸小檗堿3種主要生物堿的高效液相色譜法測(cè)定方法,3種生物堿濃度分別在4.3886-87.7716(r=0.9997).3.6649～73.2982(r=0.9998).29.5994～591.9876(r=0.9999) μg·mL~(-1)范圍內(nèi)線性關(guān)系良好(n=8)；平均加樣回收率(n=9)分別為97.97%(RSD=1.02%)、100.70%(RSD=1.42%)、98.51%(RSD=0.86%),建立的3.種生物堿含量方法準(zhǔn)確度與重復(fù)性良好,可作為藏藥小檗膏提取物的質(zhì)量控制方法。4.篩選出大孔吸附樹(shù)脂純化工藝的最佳工藝參數(shù)為：采用HPD100型大孔吸附樹(shù)脂,上樣液總生物堿濃度為3 mg.mL~(-1),上樣速度為1 mL·min-1,用4 BV的純化水洗脫除去水溶性雜質(zhì),再用7 BV30%乙醇溶液以2 mL·min-1的流速洗脫,收集流出液,濃縮、干燥成為粉末,即為藏藥小檗皮提取物Ⅰ的總生物堿有效部位(藏藥小檗皮提取物Ⅱ),以總生物堿計(jì)算,以紫外分光光度法和高效液相色譜法兩種測(cè)定方法含量均高于50%,為后期進(jìn)一步的劑型選擇、質(zhì)量控制、臨床試驗(yàn)等研究與開(kāi)發(fā)提供基礎(chǔ)。結(jié)論藏藥小檗皮中以小檗堿為代表的生物堿類(lèi)成分對(duì)糖尿病視網(wǎng)膜病變具有良好的防治作用,預(yù)測(cè)該類(lèi)成分可能在腸道部位吸收較好,本實(shí)驗(yàn)制備所得藏藥小檗皮提取物Ⅱ可作為后續(xù)防治糖尿病視網(wǎng)膜病變口服腸溶固體制劑原料。
[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.
【學(xué)位授予單位】：成都中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：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.
【學(xué)位授予單位】：成都中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R29
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