血竭微粒体系制备及粒径与吸收的相关性研究
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摘要
目的本文以血竭为研究对象,通过改善辅料、溶剂、温度等因素制成从纳米到微米等不同粒径的血竭自组装制剂,制剂的粒径由马尔文激光粒度仪及透射式电子显微镜测得；将不同粒径的血竭自组装制剂灌胃于小鼠体内用平衡研究法考察其生物利用度；旨在考察不同粒径血竭制剂的吸收情况与其粒径大小之间的相关性,选择最优粒径的制剂以提高血竭生物利用度,提高药效,克服血竭在水中难溶临床难以提高生物利用度的难题。
方法不同粒径血竭自组装制剂的研究：以50%,60%,70%,80%,90%,100%的乙醇溶液为主要分散基质制得血竭纳米混悬液,观察在以乙醇为主要分散基质的血竭纳米混悬液中加入PEG的种类与量对其粒径的影响；制备以不同分子量的PEG为载体的血竭固体分散体并测得粒径；制得以泊洛萨姆为载体的血竭固体分散体并测得粒径；制得以PEG和泊洛萨姆不同比例混合物为载体的血竭固体分散体,考察不同比例PEG与泊洛萨姆混合物对粒径的影响；考察载药量对血竭粒径的影响；考察加水量对血竭粒径的影响；考察水温对血竭粒径的影响。
从制剂研究中选取7个不同粒径的血竭制剂,以小鼠体内平衡研究法研究血竭制剂的吸收情况,高效液相电化学检测(HPLC-ECD)法测定小鼠粪便中龙血素A、B及其他指纹峰的含量,比较7个不同粒径的血竭制剂的吸收情况与粒径的相关性。结果不同粒径血竭制剂制备结果：以不同浓度乙醇为主要分散基质的血竭纳米混悬液,常温下粒径均在200nm左右,粒径不受乙醇浓度的影响。在以乙醇为主要分散基质的血竭纳米混悬液中加入助乳化剂PEG,当低温时加入PEG会使溶液中析出物更少且析出物粒径更均匀,而在室温时,溶液中不形成析出物,溶液粒径随着加入PEG分子量的增大粒径增大,当加入PEG600时粒径约为300nm,当加入PEG4000时粒径约为2μm;以不同分子量的PEG为载体制备血竭固体分散体时,随着PEG分子量的大小变化,粒径变化不呈规律性,经电子显微镜测定平均粒径约为183nm；以泊洛萨姆为载体制得血竭固体分散体时,制成的溶液澄明,可能已形成胶束；以泊洛萨姆与PEG4000混合物为载体制备血竭固体分散体时,当泊洛萨姆的比例超过50%能形成澄明的溶液,当PEG4000:泊洛萨姆=60:40,70:30,75:25,80:20时,平均粒径分别为29,45,59,123nm.即随着PEG百分含量变大,粒径在一定范围内变大；当制备固体分散体时,载体能承载的药量是一定的,一般1g载体最多能使0.2g的血竭粉末分散均匀；加水量不对血竭制剂的粒径造成影响；温度对血竭纳米自组装制剂的粒径影响较大,温度低于室温时,溶液中常出现大小不一的析出物。
选取7个不同粒径的血竭制剂,以小鼠平衡研究法研究血竭制剂的吸收情况,HPLC-ECD法测定小鼠粪便中龙血素A、B及其他指纹峰的残留情况,结果平均粒径小于2.6μm的样品龙血素A、B的吸收百分比和100.83μm样品的吸收百分比相比较,前者约为后者的两倍,其他指纹图谱峰也是随着粒径的减小,吸收百分比增大。从100.83μm到2.6μm这个粒径范围内表现为最明显的随着粒径的减小,吸收率增加,从2.6μm以后再减小血竭自组装制剂的粒径的话,吸收率增加的幅度较小。
结论制剂粒径大小是影响血竭吸收的关键,在2.6μm以上,粒径越小,血竭吸收百分比越大；2.6μm以下的粒径,吸收百分比增加的幅度较小,吸收可能已经达到饱和。吸收率与粒径呈线性相关,粒径越小,吸收率越大。本论文表明将龙血竭药材制成小粒径自组装制剂后,生物利用度明显提高,对血竭剂型改革具有一定的意义。
Objective:
In this paper, different diameter Dragon's blood preparation from nanometer to micrometer was prepared by changing the auxiliary、solvent、temperature and other factors. The diameter of the preparations were measured by the Malvern laser size analyzer and electron microscope. After Dragon's blood preparation with different diameter were given to mice ig, its bioavailability would be texted with the balance research method.This paper would text its correlation between Dragon's blood diameter and its absorption,select the optimal diameter of Dragon's blood preparation to enhance its bioavailability,improve its efficacy and overcome Dragon's blood's poor water-solubility,improve its bioavailability in clinical.
Method:
The study of Dragon's blood preparation with different diameter:
Dragon's blood nanometer suspension,taking 50%.60%.70%.80%.90%.100% ethanol as the main dispersion matrix system, was made up.Observed its influence to diameter by adding different type or quantity PEG to the Dragon's blood nanometer suspension taking ethanol as the main dispersion matrix system; Dragon's blood solid dispersion with different molecular weight's PEG as carrier was prepared,and measured its diameter; Dragon's blood solid dispersion with poloxamer as carrier was prepared,and measured its diameter; Dragon's blood solid dispersion with PEG and poloxamer mixtures of different ratios as carrier was prepared, and measured its diameter, examined the influence to the diameter of different ratios; Examined the influence of drug loading to the Dragon's blood diameter; Examined the influence of watering quantity to the Dragon's blood diameter; Examined the influence of tempeature to the Dragon's blood diameter.
Dragon's blood preparation of 7 different diameter were selected,and studied its absorption in mice with the balance research method. Loureirin A. B and other fingerprint peak levels in mice feces were determined by HPLC-electrochemical determination(HPLC-ECD),compared its correlation between Dragon's blood diameter and its absorption.
Result:
The results of the prepared of different diameter Dragon's blood:
The Dragon's blood nanometer suspension's diameter with different concerntrations of ethanol as the main dispersion matrix system was about 200nm in room temperature, the diameter was not influence of ethanol concerntration. There was auxiliary PEG adding to the Dragon's blood nanometer suspension with ethanol as the main dispersion matrix system, when the low temperature, adding PEG would cause less precipitation and more uniform diameter in solution, when at room temperature,there was no precipition in solution,the diameter was increasing with the adding PEG molecular increased. The diameter was about 300nm when adding PEG600, the diameter was about 2μm when adding PEG4000. The average diameter of Dragon's blood solid dispersion with PEG as carrier was about 183nm,measured by electron microscope. The diameter did not change regulary with PEG molecular weight change. Poloxamer as carrier to get Dragon's blood solid dispersion, the solution made of clarity, may form micelle. There was Dragon's blood solid dispersion with the mixture of poloxamer and PEG4000 as carrier, when the ratio of poloxamer was more than 50%,the solution was clarity, when the ratio was PEG4000:poloxamer=60:40,70:30,75:25,80:20, the average diameter was about 29,45, 59,123nm,namely along with PEG the percentage content was larger, the diameter was larger in certain rang. The carrier carried the drug was certain, when prepared Dragon's blood solid dispersion, generally 1g carrier can support 0.2g drug at most; The watering quantity did not influence Dragon's blood diameter; Temperature effected on the diameter of Dragon's blood preparation, when temperature was lower than room temperature, precipitates of different size often appeared in solution.
This experiment selected Dragon's blood preparation of 7 different diameter, studied its absorption in mice with the balance research method. Loureirin A、B and other fingerprint peak levels in mice feces were determined by HPLC-ECD. The results showed that, Loureirin A、B absorption percentage in the sample that average diameter was smaller than 2.6μm was twice than in the sample that average diameter was about 100.83μm.Other fingerprint peak's absorption percentage also increased with the diameter decreased. From 2.6μm to100.83μm, the performance was most obvious with diameter decreased, the absorption rat increased. When the diameter was less than 2.6μm, futher reduce the diameter of Dragon's blood preparation,then a less extent increase in absorption rate.
Conclusion:Diameter of the Dragon's blood preparation was key to its absorption. When the diameter was more than 2.6μm, the smaller the diameter, the greater percentage of Dragon's blood absorption. When the diameter is less than 2.6μm, the absorption percentage increases scope is small, the absorption possibility already achieved saturated. Absorption rate was correlated with the diameter, the smaller the diameter, the absorption rate is higher. This paper showed that, the bioavailability increased significantly after made small diameter of Dragon's blood. There was certain significance to the formulation reform of Dragon's blood.
方法不同粒径血竭自组装制剂的研究：以50%,60%,70%,80%,90%,100%的乙醇溶液为主要分散基质制得血竭纳米混悬液,观察在以乙醇为主要分散基质的血竭纳米混悬液中加入PEG的种类与量对其粒径的影响；制备以不同分子量的PEG为载体的血竭固体分散体并测得粒径；制得以泊洛萨姆为载体的血竭固体分散体并测得粒径；制得以PEG和泊洛萨姆不同比例混合物为载体的血竭固体分散体,考察不同比例PEG与泊洛萨姆混合物对粒径的影响；考察载药量对血竭粒径的影响；考察加水量对血竭粒径的影响；考察水温对血竭粒径的影响。
从制剂研究中选取7个不同粒径的血竭制剂,以小鼠体内平衡研究法研究血竭制剂的吸收情况,高效液相电化学检测(HPLC-ECD)法测定小鼠粪便中龙血素A、B及其他指纹峰的含量,比较7个不同粒径的血竭制剂的吸收情况与粒径的相关性。结果不同粒径血竭制剂制备结果：以不同浓度乙醇为主要分散基质的血竭纳米混悬液,常温下粒径均在200nm左右,粒径不受乙醇浓度的影响。在以乙醇为主要分散基质的血竭纳米混悬液中加入助乳化剂PEG,当低温时加入PEG会使溶液中析出物更少且析出物粒径更均匀,而在室温时,溶液中不形成析出物,溶液粒径随着加入PEG分子量的增大粒径增大,当加入PEG600时粒径约为300nm,当加入PEG4000时粒径约为2μm;以不同分子量的PEG为载体制备血竭固体分散体时,随着PEG分子量的大小变化,粒径变化不呈规律性,经电子显微镜测定平均粒径约为183nm；以泊洛萨姆为载体制得血竭固体分散体时,制成的溶液澄明,可能已形成胶束；以泊洛萨姆与PEG4000混合物为载体制备血竭固体分散体时,当泊洛萨姆的比例超过50%能形成澄明的溶液,当PEG4000:泊洛萨姆=60:40,70:30,75:25,80:20时,平均粒径分别为29,45,59,123nm.即随着PEG百分含量变大,粒径在一定范围内变大；当制备固体分散体时,载体能承载的药量是一定的,一般1g载体最多能使0.2g的血竭粉末分散均匀；加水量不对血竭制剂的粒径造成影响；温度对血竭纳米自组装制剂的粒径影响较大,温度低于室温时,溶液中常出现大小不一的析出物。
选取7个不同粒径的血竭制剂,以小鼠平衡研究法研究血竭制剂的吸收情况,HPLC-ECD法测定小鼠粪便中龙血素A、B及其他指纹峰的残留情况,结果平均粒径小于2.6μm的样品龙血素A、B的吸收百分比和100.83μm样品的吸收百分比相比较,前者约为后者的两倍,其他指纹图谱峰也是随着粒径的减小,吸收百分比增大。从100.83μm到2.6μm这个粒径范围内表现为最明显的随着粒径的减小,吸收率增加,从2.6μm以后再减小血竭自组装制剂的粒径的话,吸收率增加的幅度较小。
结论制剂粒径大小是影响血竭吸收的关键,在2.6μm以上,粒径越小,血竭吸收百分比越大；2.6μm以下的粒径,吸收百分比增加的幅度较小,吸收可能已经达到饱和。吸收率与粒径呈线性相关,粒径越小,吸收率越大。本论文表明将龙血竭药材制成小粒径自组装制剂后,生物利用度明显提高,对血竭剂型改革具有一定的意义。
Objective:
In this paper, different diameter Dragon's blood preparation from nanometer to micrometer was prepared by changing the auxiliary、solvent、temperature and other factors. The diameter of the preparations were measured by the Malvern laser size analyzer and electron microscope. After Dragon's blood preparation with different diameter were given to mice ig, its bioavailability would be texted with the balance research method.This paper would text its correlation between Dragon's blood diameter and its absorption,select the optimal diameter of Dragon's blood preparation to enhance its bioavailability,improve its efficacy and overcome Dragon's blood's poor water-solubility,improve its bioavailability in clinical.
Method:
The study of Dragon's blood preparation with different diameter:
Dragon's blood nanometer suspension,taking 50%.60%.70%.80%.90%.100% ethanol as the main dispersion matrix system, was made up.Observed its influence to diameter by adding different type or quantity PEG to the Dragon's blood nanometer suspension taking ethanol as the main dispersion matrix system; Dragon's blood solid dispersion with different molecular weight's PEG as carrier was prepared,and measured its diameter; Dragon's blood solid dispersion with poloxamer as carrier was prepared,and measured its diameter; Dragon's blood solid dispersion with PEG and poloxamer mixtures of different ratios as carrier was prepared, and measured its diameter, examined the influence to the diameter of different ratios; Examined the influence of drug loading to the Dragon's blood diameter; Examined the influence of watering quantity to the Dragon's blood diameter; Examined the influence of tempeature to the Dragon's blood diameter.
Dragon's blood preparation of 7 different diameter were selected,and studied its absorption in mice with the balance research method. Loureirin A. B and other fingerprint peak levels in mice feces were determined by HPLC-electrochemical determination(HPLC-ECD),compared its correlation between Dragon's blood diameter and its absorption.
Result:
The results of the prepared of different diameter Dragon's blood:
The Dragon's blood nanometer suspension's diameter with different concerntrations of ethanol as the main dispersion matrix system was about 200nm in room temperature, the diameter was not influence of ethanol concerntration. There was auxiliary PEG adding to the Dragon's blood nanometer suspension with ethanol as the main dispersion matrix system, when the low temperature, adding PEG would cause less precipitation and more uniform diameter in solution, when at room temperature,there was no precipition in solution,the diameter was increasing with the adding PEG molecular increased. The diameter was about 300nm when adding PEG600, the diameter was about 2μm when adding PEG4000. The average diameter of Dragon's blood solid dispersion with PEG as carrier was about 183nm,measured by electron microscope. The diameter did not change regulary with PEG molecular weight change. Poloxamer as carrier to get Dragon's blood solid dispersion, the solution made of clarity, may form micelle. There was Dragon's blood solid dispersion with the mixture of poloxamer and PEG4000 as carrier, when the ratio of poloxamer was more than 50%,the solution was clarity, when the ratio was PEG4000:poloxamer=60:40,70:30,75:25,80:20, the average diameter was about 29,45, 59,123nm,namely along with PEG the percentage content was larger, the diameter was larger in certain rang. The carrier carried the drug was certain, when prepared Dragon's blood solid dispersion, generally 1g carrier can support 0.2g drug at most; The watering quantity did not influence Dragon's blood diameter; Temperature effected on the diameter of Dragon's blood preparation, when temperature was lower than room temperature, precipitates of different size often appeared in solution.
This experiment selected Dragon's blood preparation of 7 different diameter, studied its absorption in mice with the balance research method. Loureirin A、B and other fingerprint peak levels in mice feces were determined by HPLC-ECD. The results showed that, Loureirin A、B absorption percentage in the sample that average diameter was smaller than 2.6μm was twice than in the sample that average diameter was about 100.83μm.Other fingerprint peak's absorption percentage also increased with the diameter decreased. From 2.6μm to100.83μm, the performance was most obvious with diameter decreased, the absorption rat increased. When the diameter was less than 2.6μm, futher reduce the diameter of Dragon's blood preparation,then a less extent increase in absorption rate.
Conclusion:Diameter of the Dragon's blood preparation was key to its absorption. When the diameter was more than 2.6μm, the smaller the diameter, the greater percentage of Dragon's blood absorption. When the diameter is less than 2.6μm, the absorption percentage increases scope is small, the absorption possibility already achieved saturated. Absorption rate was correlated with the diameter, the smaller the diameter, the absorption rate is higher. This paper showed that, the bioavailability increased significantly after made small diameter of Dragon's blood. There was certain significance to the formulation reform of Dragon's blood.
引文
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