难溶性药物理化性质对其纳米混悬剂生物利用度的影响
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摘要
BCS Ⅱ类药物的纳米化是增加其溶出速度以及生物利用度的有效手段。本研究选取盐酸瑞伐拉赞为模型药物,通过高压均质法制备了盐酸瑞伐拉赞的纳米混悬剂,考察了制备工艺对其混悬剂粒径的影响,并对盐酸瑞伐拉赞的纳米混悬剂、微米混悬剂和粗混悬剂的大鼠体内药动学进行了考察。结果显示,盐酸瑞伐拉赞纳米混悬剂的大鼠体内生物利用度显著高于其微米混悬剂和粗混悬剂,证明了药物粒径会影响盐酸瑞伐拉赞的体内吸收,纳米混悬剂是提高盐酸瑞伐拉赞的生物利用度的有效手段之一。
在上述研究基础上,以分子量、熔点、loge和分子极性表面积等理化性质均不相同的BCS Ⅱ类药物阿苯达唑、非诺贝特、伊曲康唑、普罗布考和盐酸瑞伐拉赞为模型药物研究水难溶性药物的物理化学性质对其纳米混悬剂体内吸收的影响。本研究以泊洛沙姆188(poloxamer188)为唯一的稳定剂,采用高压均质法制备粒径约为450nn (428nm-463nm)的药物纳米混悬剂,以排除制备工艺、处方因素和药物粒径对纳米混悬剂体内吸收的干扰。采用差示扫描量热法(DSC)和粉末X射线衍射法(PXRD)对上述药物纳米晶体进行晶体学研究,结果表明药物纳米晶体与原料药粉末晶形相同,证实纳米混悬剂的制备过程并没有改变药物的晶形,从而排除药物晶形对药物吸收的干扰。在此基础上,本研究考察了药物纳米混悬剂和微米混悬剂在溶出介质FaSSIF中的溶出度和大鼠体内药物动力学行为。结果表明药物的纳米混悬剂较其微米混悬剂具有更高的溶出速度和生物利用度,并且发现120min时药物纳米混悬剂和微米混悬剂溶出量的比值的dissolvednano/dissolvedmicro与两种混悬剂AUC0-t的比值AUC0-t nano/AUC0-t micro呈显著线性关系,证明药物纳米混悬剂在FaSSIF中的溶出行为能在一定程度上预测其在体内的吸收情况。FaSSIF可能是研究难溶性药物纳米混悬剂体内外相关性的适宜溶出介质。
为了得到药物物理化学性质与其纳米混悬剂体内吸收的关系,本研究借助于统计学方法和Matlab2009可视化软件考察了药物的物理化学性质(分子量、熔点、logP和分子极性表面积)与药物纳米混悬剂生物利用度之间的关系。结果表明当药物的熔点越低、logP值在5左右、分子极性表面积值在50-60A2之间时药物纳米混悬剂的AUC0-t越大,即生物利用度越高。
综上所述,粒径是影响难溶性药物吸收的重要因素,纳米混悬剂能够提高药物的体内生物利用度；药物的熔点、logP和分子极性表面积对难溶性药物纳米混悬剂的体内吸收影响很大。本课题为后续研究理化性质对难溶性药物纳米混悬剂体内吸收的影响提供了新的思路。
Nanosizing of BCS II drugs is an effective way to improve their dissolution rate and bioavailability. Revaprazan hydrochloride nanosuspension was prepared by high pressure homogenization to investigate whether the the nanosuspension strategy is a good way to improve its bioavailability. The influence of homogenization pressure and cycles on particle size were studied as well. Higher pressure and more homogenization cycles favored the decrease of drug particle size, but there were optimal pressure and cycle numbers beyond which the particle size would not decrease. Three different sized revaprazan hydrochloride suspensions were prepared and the in vitro and in vivo evaluations were carried out. The nanosuspensions gained the highest dissolution rate and bioavailability. The results reveal that drug particle size affects the drug absorption and the nanosuspension could improve the bioavailability of revaprazan hydrochloride.
In order to investigate the influence of drug physicochemical properties on bioavailability of water insoluble drug nanosuspensions, albendazole, fenofibrate, itraconazole, probucol and revaprazan hydrochloride were selected as model drugs. Due to the poor water solubility the bioavailability of the model drugs are very low. As BSC II drugs their bioavailability could be improved by nanosuspension strategy. The drug nanosuspensions were prepared by high pressure homogenization using the same stabilizer(poloxamer188) and were similar in particle size(around450nm). So the interference from stabilizer and particle size on drug absorption were excluded. DSC and powder X-ray diffraction study showed that the crystalline state of the freeze dried nanoparticles did not change. As a result the interference of crystalline state on drug absorption were excluded either. Based on this the in vitro dissolution in FaSSIF and in vivo bioavailability study in rats were performed. The results showed that the nanosuspensions demonstrated higher dissolution rate and bioavailability compared with the corresponding microsuspensions. Besides, it was found that the dissolvednano/dissolvedmicro in120min was significantly correlated with AUC0-t nano/AUC0-t micro, which revealed that dissolution in FaSSIF could in some extent predict the absorption of the drug nanosuspension. FaSSIF may be a suitable dissolution medium for in vitro-in vivo correlation study of drug nanosuspensions.
In order to find the relationship between the bioavailability of the drug nanosuspensions and the drug physicochemical properties (molecular weight, melting point, logP and polar surface area) the statistical analysis were performed. After multi-linear regression analysis and interpolated surface analysis it was found that the drug with smaller melting point, logP value around5and polar surface area value in the range of50-60would gain higher AUC0-t nano and accordingly higher bioavailability.
In summary, particle size played an important in drug absorption and melting point, logP and polar surface area were factors that influence the bioavailability of water insoluble drug nanosuspensions in this study. This study gives an excellent resolution in studying the influence of drug physicochemical properties on bioavailability of water insoluble drug nanosuspensions.
在上述研究基础上,以分子量、熔点、loge和分子极性表面积等理化性质均不相同的BCS Ⅱ类药物阿苯达唑、非诺贝特、伊曲康唑、普罗布考和盐酸瑞伐拉赞为模型药物研究水难溶性药物的物理化学性质对其纳米混悬剂体内吸收的影响。本研究以泊洛沙姆188(poloxamer188)为唯一的稳定剂,采用高压均质法制备粒径约为450nn (428nm-463nm)的药物纳米混悬剂,以排除制备工艺、处方因素和药物粒径对纳米混悬剂体内吸收的干扰。采用差示扫描量热法(DSC)和粉末X射线衍射法(PXRD)对上述药物纳米晶体进行晶体学研究,结果表明药物纳米晶体与原料药粉末晶形相同,证实纳米混悬剂的制备过程并没有改变药物的晶形,从而排除药物晶形对药物吸收的干扰。在此基础上,本研究考察了药物纳米混悬剂和微米混悬剂在溶出介质FaSSIF中的溶出度和大鼠体内药物动力学行为。结果表明药物的纳米混悬剂较其微米混悬剂具有更高的溶出速度和生物利用度,并且发现120min时药物纳米混悬剂和微米混悬剂溶出量的比值的dissolvednano/dissolvedmicro与两种混悬剂AUC0-t的比值AUC0-t nano/AUC0-t micro呈显著线性关系,证明药物纳米混悬剂在FaSSIF中的溶出行为能在一定程度上预测其在体内的吸收情况。FaSSIF可能是研究难溶性药物纳米混悬剂体内外相关性的适宜溶出介质。
为了得到药物物理化学性质与其纳米混悬剂体内吸收的关系,本研究借助于统计学方法和Matlab2009可视化软件考察了药物的物理化学性质(分子量、熔点、logP和分子极性表面积)与药物纳米混悬剂生物利用度之间的关系。结果表明当药物的熔点越低、logP值在5左右、分子极性表面积值在50-60A2之间时药物纳米混悬剂的AUC0-t越大,即生物利用度越高。
综上所述,粒径是影响难溶性药物吸收的重要因素,纳米混悬剂能够提高药物的体内生物利用度；药物的熔点、logP和分子极性表面积对难溶性药物纳米混悬剂的体内吸收影响很大。本课题为后续研究理化性质对难溶性药物纳米混悬剂体内吸收的影响提供了新的思路。
Nanosizing of BCS II drugs is an effective way to improve their dissolution rate and bioavailability. Revaprazan hydrochloride nanosuspension was prepared by high pressure homogenization to investigate whether the the nanosuspension strategy is a good way to improve its bioavailability. The influence of homogenization pressure and cycles on particle size were studied as well. Higher pressure and more homogenization cycles favored the decrease of drug particle size, but there were optimal pressure and cycle numbers beyond which the particle size would not decrease. Three different sized revaprazan hydrochloride suspensions were prepared and the in vitro and in vivo evaluations were carried out. The nanosuspensions gained the highest dissolution rate and bioavailability. The results reveal that drug particle size affects the drug absorption and the nanosuspension could improve the bioavailability of revaprazan hydrochloride.
In order to investigate the influence of drug physicochemical properties on bioavailability of water insoluble drug nanosuspensions, albendazole, fenofibrate, itraconazole, probucol and revaprazan hydrochloride were selected as model drugs. Due to the poor water solubility the bioavailability of the model drugs are very low. As BSC II drugs their bioavailability could be improved by nanosuspension strategy. The drug nanosuspensions were prepared by high pressure homogenization using the same stabilizer(poloxamer188) and were similar in particle size(around450nm). So the interference from stabilizer and particle size on drug absorption were excluded. DSC and powder X-ray diffraction study showed that the crystalline state of the freeze dried nanoparticles did not change. As a result the interference of crystalline state on drug absorption were excluded either. Based on this the in vitro dissolution in FaSSIF and in vivo bioavailability study in rats were performed. The results showed that the nanosuspensions demonstrated higher dissolution rate and bioavailability compared with the corresponding microsuspensions. Besides, it was found that the dissolvednano/dissolvedmicro in120min was significantly correlated with AUC0-t nano/AUC0-t micro, which revealed that dissolution in FaSSIF could in some extent predict the absorption of the drug nanosuspension. FaSSIF may be a suitable dissolution medium for in vitro-in vivo correlation study of drug nanosuspensions.
In order to find the relationship between the bioavailability of the drug nanosuspensions and the drug physicochemical properties (molecular weight, melting point, logP and polar surface area) the statistical analysis were performed. After multi-linear regression analysis and interpolated surface analysis it was found that the drug with smaller melting point, logP value around5and polar surface area value in the range of50-60would gain higher AUC0-t nano and accordingly higher bioavailability.
In summary, particle size played an important in drug absorption and melting point, logP and polar surface area were factors that influence the bioavailability of water insoluble drug nanosuspensions in this study. This study gives an excellent resolution in studying the influence of drug physicochemical properties on bioavailability of water insoluble drug nanosuspensions.
引文
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