大黄酚—羟丙基-β-环糊精包合物的制备及药代动力学研究
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摘要
大黄酚(Chrysophanol,Chry)是大黄、虎杖、何首乌等蓼科植物中的一种有效单体,属于蒽醌类化合物,具有抗菌、止血、抗癌、止咳、利尿等药理作用。根据文献报道,大黄酚还能消除体内自由基,有明显的抗衰老和促进学习记忆的作用。大黄酚属于脂溶性化合物,易溶于甲醇、乙醇、丙酮等有机溶剂。由于大黄酚在水中溶解度极小,生物利用度不高,限制了大黄酚在临床中的应用。因此,为了拓宽大黄酚的应用范围,为临床用药提供可选择的应用剂型,本课题研究了大黄酚的包合技术。包合技术由于能极大地提高难溶性药物的溶解度,而广泛应用于难溶性药物的剂型研究领域。本课题选择羟丙基-β-环糊精为包合材料,采用最佳的制备方法及工艺将大黄酚制成包合物,以增加其在水中的溶解度,并考察大黄酚包合物的稳定性、体外溶出度。同时观察大黄酚包合物在动物体内的药代动力学特征,得到药动学参数,为大黄酚包合物注射剂的研制提供依据。
大黄酚包合物制备方法及工艺研究:以大黄酚-羟丙基-β-环糊精包合物的包合率与收得率为指标,在相同的工艺条件下,比较搅拌法、研磨法与超声法的包合效果,以确定较适宜的制备方法。采用正交试验对制备中的主要工艺条件进行筛选,考察大黄酚与羟丙基-β-环糊精质量比、溶剂浓度、包合时间及温度等因素对包合过程的影响,优化羟丙基-β-环糊精包合大黄酚的条件。同时采用紫外分光光度法、薄层色谱法及相溶解度法验证包合物的形成。结果显示:大黄酚与羟丙基-β-环糊精的最佳包合工艺是:大黄酚与羟丙基-β-环糊精的质量比为1:60,溶剂乙醇的浓度为50%,包合时间2h,包合温度是30℃,大黄酚-羟丙基-β-环糊精包合物包合率可达64.11%。相溶解度曲线为AL型。当HP-β-CD的质量分数为20%时,可使Chry溶解度增大102.66倍。
大黄酚包合物稳定性及体外溶出度研究:比较大黄酚与大黄酚包合物的光稳定性、热稳定性和湿稳定性。采用动态透析技术研究大黄酚包合物的体外溶出度,观察其释药性能。结果显示:在光、热及湿的因素影响下,大黄酚包合物的稳定性较单体药物有显著提高。大黄酚包合物的体外溶出性能良好,显示出一定的缓释特征。
动物体内的药代动力学研究:选用两种动物分别考察大黄酚制剂的药代动力学,给予家兔耳缘静脉注射大黄酚溶液或大黄酚包合物水溶液,连续测定各时间点血浆中药物含量,分析药动学参数和隔室模型。给予小鼠尾静脉注射大黄酚溶液或大黄酚包合物水溶液,在不同时间点测定小鼠血浆、心、肝、脑、脾、肺、肾中大黄酚的含量,研究大黄酚及大黄酚包合物在小鼠体内的组织分布特征。结果显示:大黄酚及包合物在家兔体内的药动学过程均符合二室模型,两者的平均消除半衰期(t1/2β)分别为9.093h和13.075h,推测包合物的消除过程较大黄酚稍慢。采用两样本t检验对大黄酚及包合物在小鼠体内各个组织的含量进行统计学分析,小鼠静脉注射包合物与注射大黄酚比较,在血、肝及脑中的药物含量有显著性差异(p<0.05)。
综上所述,采用优化的工艺条件制备大黄酚-羟丙基-β-环糊精包合物,包合率高,工艺稳定,操作简单。大黄酚适宜用羟丙基-β-环糊精包合,增溶效果明显。大黄酚包合物显著提高了药物的稳定性及体外溶出度。大黄酚包合物在家兔体内的药动学过程为二室模型。大黄酚制成包合物后可显著提高小鼠脑中的药物含量。
Chrysophanol(Chry) is an effective monomer in Polygonaceae plantssuch as rhubarb, Polygonum cuspidatum, Polygonum multiflorum, whichbelongs to anthraquinone compounds and has antibacterial action,hemostasis, anticancer effect, relieving a cough, diuretic and otherpharmacological effects. According to the literatures, chrysophanol caneliminate free radicals and has obvious anti-aging and the promotion oflearning and memory. Chrysophanol is fat-soluble compound and soluble inmethanol, ethanol, acetone and other organic solvents. As chrysophanolhas a very small solubility in water and its bioavailability is not high, itsclinical application is limited. Therefore, inclusion technology ofchrysophanol was studied in the subject in order to broaden the applicationscope of chrysophanol and provide alternative formulation for clinicalapplication of drug. Inclusion technique can greatly improve the solubilityof insoluble drug, which is widely used in formulations research ofinsoluble drugs. In this paper, using hydroxypropyl-β-cyclodextrin (HP-β-CD) as the inclusion material, chrysophanol was made into inclusion complex by the best preparation method and technics to increaseits solubility in water, and the stability and dissolution in vitro ofchrysophanol inclusion complex were examined. The pharmacokineticcharacteristics of chrysophanol inclusion complex were studied in animalsas well . All the parameters can provide the basis for the development ofchrysophanol inclusion complex injections.
The inclusion ratio and recovery of chrysophanol inclusion complexwere adopted as the observation criteria and the optimal preparation
method was decided by comparing the inclusion effect of stirring method,grinding method and supersonic method in the same technics conditions.The technology conditions of preparation were screened by the orthogonaltest. The multiple factors including weight ratio of chrysophanol andHP-β-CD, concentration of solvent, time and temperature were investigated in the inclusion process to optimize the preparation conditions ofChry-HP-β-CD. The inclusion complex was identified by ultraviolet and visible spectrophotometry(UV-vis), thin-layer chromatography(TLC) andphase solubility. The result showed that the optimumpreparation conditionsfor inclusion were established as follows: the weight ratio of chrysophanoland hydroxyphrophy-β-cyclodextrin was 1:60, concentration of ethanol was 50%, temperature was 30℃and timewas 2h. The inclusion ratio ofChry-HP-β-CD was 64.11%. The phase solubility curve was AL type. Whenthe quality fraction of HP-β-CD was 20%, the solubility of chrysophanol increased 102.66 times.
Study on the stability and dissolution in vitro: The chrysophanolwas compared with the chrysophanol inclusion complex to study both lightstability, thermal stability and wet stability. The dissolution in vitro wasresearched by dynamic dialysis technology to observe the release propertiesof Chry-HP-β-CD. The result showed that the stability of Chry-HP-β-CD was increased more significantly than that of chrysophanol under the hightemperature, high humidity and light conditions. Chry-HP-β-CD had good performance in vitro dissolution showing a degree of sustained-releasecharacteristics.
Study on pharmacokinetics in animals: Two kinds of animal wereused to investigate the pharmacokinetics of chrysophanol preparetion. Therabbits were injected intravenously chrysophanol or Chry-HP-β-CD, and then plasma drug content was measured at different time points andStudy on the preparation methods and technics of chrysophanolhydroxypropyl-β-cyclodextrin inclusion complex(Chry-HP-β-CD): pharmacokinetic parameters and the compartment model were analyzed.The mice were injected chrysophanol or Chry-HP-β-CD in tail vein and some tissues such as plasma, heart, liver, brain, spleen, lung, kidney ofmice were taken at different time points to determine the content ofchrysophanol and study tissue distribution characteristics of chrysophanoland Chry-HP-β-CD in mice. The result showed that the pharmacokinetics of chrysophanol and Chry-HP-β-CD were two-compartment models in rabbits. The average half-life for elimination phase (t1/2β) of both was9.093h and 13.075h respectively . It was speculated that the eliminationprocess of Chry-HP-β-CD was slightly slower than that of chrysophanol. Two-sample t-test was used to statistically analyze the content ofchrysophanol and Chry-HP-β-CD in various tissues of mice. Through comparing chrysophanol and Chry-HP-β-CD with intravenous injection in mice, the content of chrysophanol in the blood, liver and brain had asignificant difference(p<0.05).
In summary, the optimized technology conditions are stable and simpleand have the high inclusion rate. HP-β-CD is fit to include chrysophanol and the solubilization effect is significant. Chry-HP-β-CD significantly improved the stability and in vitro dissolution of drugs. Chry-HP-β-CD is two-compartment pharmacokinetic model in rabbits. Chry-HP-β-CD can significantly improve the content of drugs in brains of mice.
大黄酚包合物制备方法及工艺研究:以大黄酚-羟丙基-β-环糊精包合物的包合率与收得率为指标,在相同的工艺条件下,比较搅拌法、研磨法与超声法的包合效果,以确定较适宜的制备方法。采用正交试验对制备中的主要工艺条件进行筛选,考察大黄酚与羟丙基-β-环糊精质量比、溶剂浓度、包合时间及温度等因素对包合过程的影响,优化羟丙基-β-环糊精包合大黄酚的条件。同时采用紫外分光光度法、薄层色谱法及相溶解度法验证包合物的形成。结果显示:大黄酚与羟丙基-β-环糊精的最佳包合工艺是:大黄酚与羟丙基-β-环糊精的质量比为1:60,溶剂乙醇的浓度为50%,包合时间2h,包合温度是30℃,大黄酚-羟丙基-β-环糊精包合物包合率可达64.11%。相溶解度曲线为AL型。当HP-β-CD的质量分数为20%时,可使Chry溶解度增大102.66倍。
大黄酚包合物稳定性及体外溶出度研究:比较大黄酚与大黄酚包合物的光稳定性、热稳定性和湿稳定性。采用动态透析技术研究大黄酚包合物的体外溶出度,观察其释药性能。结果显示:在光、热及湿的因素影响下,大黄酚包合物的稳定性较单体药物有显著提高。大黄酚包合物的体外溶出性能良好,显示出一定的缓释特征。
动物体内的药代动力学研究:选用两种动物分别考察大黄酚制剂的药代动力学,给予家兔耳缘静脉注射大黄酚溶液或大黄酚包合物水溶液,连续测定各时间点血浆中药物含量,分析药动学参数和隔室模型。给予小鼠尾静脉注射大黄酚溶液或大黄酚包合物水溶液,在不同时间点测定小鼠血浆、心、肝、脑、脾、肺、肾中大黄酚的含量,研究大黄酚及大黄酚包合物在小鼠体内的组织分布特征。结果显示:大黄酚及包合物在家兔体内的药动学过程均符合二室模型,两者的平均消除半衰期(t1/2β)分别为9.093h和13.075h,推测包合物的消除过程较大黄酚稍慢。采用两样本t检验对大黄酚及包合物在小鼠体内各个组织的含量进行统计学分析,小鼠静脉注射包合物与注射大黄酚比较,在血、肝及脑中的药物含量有显著性差异(p<0.05)。
综上所述,采用优化的工艺条件制备大黄酚-羟丙基-β-环糊精包合物,包合率高,工艺稳定,操作简单。大黄酚适宜用羟丙基-β-环糊精包合,增溶效果明显。大黄酚包合物显著提高了药物的稳定性及体外溶出度。大黄酚包合物在家兔体内的药动学过程为二室模型。大黄酚制成包合物后可显著提高小鼠脑中的药物含量。
Chrysophanol(Chry) is an effective monomer in Polygonaceae plantssuch as rhubarb, Polygonum cuspidatum, Polygonum multiflorum, whichbelongs to anthraquinone compounds and has antibacterial action,hemostasis, anticancer effect, relieving a cough, diuretic and otherpharmacological effects. According to the literatures, chrysophanol caneliminate free radicals and has obvious anti-aging and the promotion oflearning and memory. Chrysophanol is fat-soluble compound and soluble inmethanol, ethanol, acetone and other organic solvents. As chrysophanolhas a very small solubility in water and its bioavailability is not high, itsclinical application is limited. Therefore, inclusion technology ofchrysophanol was studied in the subject in order to broaden the applicationscope of chrysophanol and provide alternative formulation for clinicalapplication of drug. Inclusion technique can greatly improve the solubilityof insoluble drug, which is widely used in formulations research ofinsoluble drugs. In this paper, using hydroxypropyl-β-cyclodextrin (HP-β-CD) as the inclusion material, chrysophanol was made into inclusion complex by the best preparation method and technics to increaseits solubility in water, and the stability and dissolution in vitro ofchrysophanol inclusion complex were examined. The pharmacokineticcharacteristics of chrysophanol inclusion complex were studied in animalsas well . All the parameters can provide the basis for the development ofchrysophanol inclusion complex injections.
The inclusion ratio and recovery of chrysophanol inclusion complexwere adopted as the observation criteria and the optimal preparation
method was decided by comparing the inclusion effect of stirring method,grinding method and supersonic method in the same technics conditions.The technology conditions of preparation were screened by the orthogonaltest. The multiple factors including weight ratio of chrysophanol andHP-β-CD, concentration of solvent, time and temperature were investigated in the inclusion process to optimize the preparation conditions ofChry-HP-β-CD. The inclusion complex was identified by ultraviolet and visible spectrophotometry(UV-vis), thin-layer chromatography(TLC) andphase solubility. The result showed that the optimumpreparation conditionsfor inclusion were established as follows: the weight ratio of chrysophanoland hydroxyphrophy-β-cyclodextrin was 1:60, concentration of ethanol was 50%, temperature was 30℃and timewas 2h. The inclusion ratio ofChry-HP-β-CD was 64.11%. The phase solubility curve was AL type. Whenthe quality fraction of HP-β-CD was 20%, the solubility of chrysophanol increased 102.66 times.
Study on the stability and dissolution in vitro: The chrysophanolwas compared with the chrysophanol inclusion complex to study both lightstability, thermal stability and wet stability. The dissolution in vitro wasresearched by dynamic dialysis technology to observe the release propertiesof Chry-HP-β-CD. The result showed that the stability of Chry-HP-β-CD was increased more significantly than that of chrysophanol under the hightemperature, high humidity and light conditions. Chry-HP-β-CD had good performance in vitro dissolution showing a degree of sustained-releasecharacteristics.
Study on pharmacokinetics in animals: Two kinds of animal wereused to investigate the pharmacokinetics of chrysophanol preparetion. Therabbits were injected intravenously chrysophanol or Chry-HP-β-CD, and then plasma drug content was measured at different time points andStudy on the preparation methods and technics of chrysophanolhydroxypropyl-β-cyclodextrin inclusion complex(Chry-HP-β-CD): pharmacokinetic parameters and the compartment model were analyzed.The mice were injected chrysophanol or Chry-HP-β-CD in tail vein and some tissues such as plasma, heart, liver, brain, spleen, lung, kidney ofmice were taken at different time points to determine the content ofchrysophanol and study tissue distribution characteristics of chrysophanoland Chry-HP-β-CD in mice. The result showed that the pharmacokinetics of chrysophanol and Chry-HP-β-CD were two-compartment models in rabbits. The average half-life for elimination phase (t1/2β) of both was9.093h and 13.075h respectively . It was speculated that the eliminationprocess of Chry-HP-β-CD was slightly slower than that of chrysophanol. Two-sample t-test was used to statistically analyze the content ofchrysophanol and Chry-HP-β-CD in various tissues of mice. Through comparing chrysophanol and Chry-HP-β-CD with intravenous injection in mice, the content of chrysophanol in the blood, liver and brain had asignificant difference(p<0.05).
In summary, the optimized technology conditions are stable and simpleand have the high inclusion rate. HP-β-CD is fit to include chrysophanol and the solubilization effect is significant. Chry-HP-β-CD significantly improved the stability and in vitro dissolution of drugs. Chry-HP-β-CD is two-compartment pharmacokinetic model in rabbits. Chry-HP-β-CD can significantly improve the content of drugs in brains of mice.
引文
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37何仲贵.羟丙基-β-环糊精对药物的包合作用及对体内药物动力学的影响[M].沈阳药科大学:博士毕业论文,2003:130-131.
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37何仲贵.羟丙基-β-环糊精对药物的包合作用及对体内药物动力学的影响[M].沈阳药科大学:博士毕业论文,2003:130-131.
1邓树海,毕云生,李凌冰,等.现代药物制剂技术[M].北京:化学工业出版社,2007,97-103.
2张志荣.药剂学新技术及其在改善药物功效中的作用[J].中国药学杂志,2009,44(20):1525-1532.
3袁恒杰,范立君,贾伟.现代制剂技术在中药中的应用[J].中国医院药学杂志,2005,25(11):1066-1067.
4石小鹏,杨春娥,谬姗.药物新剂型中辅料的应用[J].中国药品标准,2007,8(4):76-77.
5李云,孙立伟,赵胜芳.β-环糊精包合技术在中药药剂中的应用[J].2009,3(1):189-191.
6陶涛.羟丙基倍他环糊精的特性及其药剂学应用[J].中国医药工业杂志, 2002, 33(6):304-308.
7 Marcus E. Brewstera, Thorsteinn Loftssonb. Cyclodextrins aspharmaceutical solubilizers [J]. Advanced Drug Delivery Reviews,2007, 59(7): 645-666.
8赵慧萍,王浩,孟祥军.β-环糊精包合技术在药学领域应用的概述[J].沈阳医学院学报,2009,11(2):120-122.
9 Cal K, Centkowska K. Use of cyclodextrins in topical formulations:practical aspects[J]. Eur J PharmBiopharm, 2008, 68(3): 467-478.
10罗恒,赵燕宜,杨明.羟丙基-β-环糊精作为注射给药的载体研究进展[J].湖南中医学院学报,2007,9(3):68-69.
11 Ali H, AI-Marzouqi, Hanan M. Elwy, Ihsan Shehadi, et al. Physico-chemical properties of antifungal drug-cyclodextrin complexesprepared by supercritical carbon dioxide and by conventionaltechniques[J]. Journal of pharmaceutical and Biomedical Analysis,2009, 49(2): 227-233.
12尤思路,高秀蓉,廖昌军.饱和水溶液法制备葛根素的β-环糊精包合物研究[J].西南军医,2008,10(4):17-19.
13顾维,许美娟,陈玉俊,等.桂枝挥发油β-环糊精包合物研究[J].时珍国医药,2001,12(3):204.
14王灵杰,郑彩虹.木犀草素羟丙基-β-环糊精包合物的制备及其鉴定[J].中国现代应用药学杂志.2006,23(6):477-479.
15吕爽,弥宏,秦明明,等.正交设计法优选β--环糊精包合蛇床子超临界二氧化碳萃取产物的工艺研究[J].时珍国医国药,2008,19(4):979-980.
16马学琴,任勇,付雪艳.羟基喜树碱/羟丙基-β-环糊精包合作用研究[J].中国新药杂志,2007,16(17):1385-1387.
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18韩光,李晶华,刘蕾,等.超声法制备穿心莲内酯-β-环糊精包合物的研究[J].中国新药杂志,2008,17(7):582-585.
19李正翔,任荣.丹皮酚-β-环糊精包合物的制备[J].中国药学杂志,2004,39(4):305-306.
20韩紫岩,王荔,张庆雷.中药制剂中丹皮酚包合工艺的研究[J].河南大学学报,2007,27(3):32-34.
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22王靖,张铁军,王文燕.羟丙基-β-环糊精对降香挥发油包合作用的研究[J].中草药,2006,37(5):700-703.
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24赵喆,王齐放.环糊精对药物包合作用的研究概况[J].药学进展,2006,30(7):299-304.
25宋静亚,赵会英.相溶解度法研究不同环糊精对蛇床子素的增溶作用[J].分析科学学报,2007,23(5):595-597.
26宋洪涛,郭涛,张跃新,等. 2-羟丙基-β-环糊精对大蒜油溶解度及稳定性的影响[J].中草药,2006,37(2):199-202.
27韩世超,杜光,张慧玲,等.苯巴比妥钠包合物的制备及其在液体制剂中的稳定性[J].中国医院药学杂志,2007,27(1):53-55.
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31邓卅,田舸,杨俊,等.阿昔洛韦包合物硬胶囊的制备及质量控制[J].中国药房,2009,20(10):775-776.
32姜立群,翟所迪,杨丽.氢化可的松-羟丙基-β-环糊精制备工艺的研究[J].中国新药杂志,2003,12(10):837.
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