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摘要 综述20年来超临界技术在植物活性成分微粉化方面的应用进展,简要说明微粉化植物活性成分的表征方法、特点及发展前景。
关键词 超临界流体;微粉化;植物活性成分;超临界溶液快速膨胀技术;超临界溶液反溶剂法制备技术
中图分类号 S567 文献标识码
A 文章编号 0517-6611(2014)05-01291-04
Abstract The research progress of supercritical technology in micronized plant active ingredients was reviewed, the characterization, feature and the future development prospects of micronized plant active ingredients were elaborated.
Key words Supercritical fluid; Micronization; Plant active ingredients; Rapid expansion of supercritical solution (RESS); Preparation of supercritical solution by antisolvent method (SAS)
植物成分分为初生代谢产物和次生代谢产物2种。初生代谢产物是指生物在生长过程中通过新陈代谢产生的,如α-酮戊二酸、柠檬酸、谷氨酸、丙氨酸等。次生代谢产物是指由次生代谢产生的一类细胞生命活动或植物生长发育正常运行的非必需的小分子有机化合物,如萜类、黄酮、生物碱、甾体、木质素、矿物质等。这些物质对人类以及各种生物具有生理促进作用。植物活性成分源于次生代谢产物。其种类多,用途广泛,大多数产物用于医药学领域的研究,已在世界成为一个分支领域。但是,很多次生代谢产物的水溶性都很低,颗粒较大,导致很难被人体吸收,使得植物活性成分的生物利用度降低。
1 植物活性成分的水溶性
植物活性成分分为单体和有效部位(混合物)。植物活性成分单体是指来源于植物的一种纯物质,具有某种活性,含量在98.5%以上,如喜树碱、紫杉醇、白藜芦醇等属于单体;植物活性成分的有效部位是與来源于植物的分子结构相似的一类物质,混合在一起具有某种活性,如茶叶、三七总皂苷、银杏和人参提取物等属于有效部位。植物活性成分单体应用十分广泛,而有效部位在我国早期应用很多,现已在国际上得到认可。越来越多新的植物活性成分存在水溶性差、溶解度低的缺点,在美国药典收载的药物中超过1/3的药物存在水溶性差的问题。如何提高这些植物活性化学物的水溶性和生物利用度,达到可接受的生物有效性,对医学领域无疑是一个重大的挑战[1]。
2 超临界技术微粉化的特点
基于超临界流体制备的活性成分微粉具有颗粒小、比表面积大、活性中心多、表面反应活性高、吸附能力强等特性,因此它拥有很多常规药物所不具备的作用。超临界微粉化是由晶体状态变成无定形态的过程,可提高微粉的溶解度和溶出速率。该过程是经过物理作用来实现微粉化的,不会改变药物的化学性质,所以微粉化以后的药物活性不变。药物通过微粉化以后,具有粒径十分微小的特点,可通过生物体内的大部分组织屏障,而且进入体内以后的吸收、分布、代谢和排泄循环系统都与传统药物不同。微粉化药物的这些特点可以改善某些传统药物在体内作用小、生物利用度低的缺点。
3 植物活性成分超临界微粉化的进展
为了全面了解近20年来植物活性成分超临界微粉化方面的研究现状,检索了国际权威数据库web of science中收录的文献,一共有54篇(表1)。从图1可以看出,1993~2007年间相关的研究报道较少,每年只有1~2篇;从2008年起,文献数大幅上升,在2011、2012年表现尤为活跃(2013年文献数较少,可能是web of science数据库收录滞后的原因)。这表明植物活性成分的微粉化在学术界越来越受到重视。通过将上述文献按照不同的指标进行量化,表现出以下特点。①5年文献数。图2a为1993~2013年间以5年为1个周期的文献比例图,其中1993~1997和1998~2002年的百分比分别为3.70%和1.85%,而2003~2007年上升为11.11%,2008~2013年大幅度提高,占总数的83.33%。②粒径大小。图2b为文献报道的微粉粒径情况,粒径在>1 μm、500~1 000 nm和<500 nm 3个粒径区间的百分数分别为43%、15%和42%,即粒径小于1 000 nm的合计占57%,表明超临界微粉化技术如今达到一个比较精细化的水平。③超临界微粉化工艺的类别。图2c是广义的SAS和RESS 2种工艺的比例图,百分数分别为70.37%和29.63%,表明植物活性成分中能溶于超临界二氧化碳的数量相对较少,绝大多数活性成分需采用SAS法微粉化。④植物活性成分的类别。图2d文献中报道的单体和混合物分布图,其中单体占79.63%,混合物为20.37%,混合物的比例也达到一个较高的水平。由于混合物含有的成分较多,对粒径和含量的控制相对困难,因而这也是该领域研究的一个难点。
4 微粉化植物活性成分的表征
微粉化植物活性成分的表征是非常重要的,目前主要集中在对其化学结构、物理结构、形貌和粒径、溶剂残留等方面。在化学结构测定方面,许多研究都采用傅氏转换红外线光谱分析仪(FTIR)和液相色谱质谱联用(LCMS)来检测和分析植物活性成分微粉化之后的化学结构是否发生变化。几乎所有的研究都表明,经过超临界微粉化的植物活性成分的化学结构没有发生变化。它是一种条件十分温和的微粉化技术,尤其适合具热敏性、易氧化等特性的植物活性成分。在物理结构测定方面,通常采用X射线粉末衍射(XRD)、差示扫描量热仪(DSC)和热重分析仪(TGA)等方法联用分析微粉化前后晶体结构的变化,即是否形成新的晶体或结晶度降低或形成无定形态,从而推测所得微粉化植物活性成分在溶解度、溶出速度、热稳定性等方面可能出现的特点。在形貌和粒径测定方面,随着检测设备的不断出现,微粉化活性成分的形貌的测定,也由早期的放大倍率只有1 000倍的光学显微镜逐渐发展成为扫描电镜、透射电镜来进行检测,目前还出现具有3维成像功能的原子力显微成像观测技术,可以实现在长、宽、高3个维度进行量化测定。在溶剂残留方面,将样品采用易挥发溶剂进行萃取,然后采用气相色谱法进行溶剂残留测定,超临界微粉化得到纯度高、无毒无害的微粉化植物活性成分,溶剂残留符合ICH规定的要求,表明这是一种“绿色环保”的微粉化技术。 5 微粉化植物活性成分的特點
采用超临界技术获得的植物活性成分因其在粒径、比表面积、晶体结构、表面电位等方面发生改变,在溶解度、生物利用度和活性方面也发生相应变化。①溶解度。活性成分微粉化后因其粒径降低,比表面积增加,可以提高其在生物体内的溶出速率和溶解度。这对于活性成分在体内快速起效是十分有利的。②生物利用度。采用超临界流体技术制备的微粉化植物活性成分,以大鼠为受试模型动物口服或注射给药、眼球取血、高效液相色谱仪血药浓度检测。大多数文献表明,其体内生物利用度与原粉相比有大幅度的提高。③活性。当植物活性成分颗粒达到纳米级水平时,随着颗粒总表面的增加,与胃肠道液体的有效面积明显增加,提高活性成分的溶出速率;在具有相同的药物效果前提下,可以减少药物用药量,减轻或消除植物活性成分的毒副作用;植物活性成分具有颗粒小、比表面积大、表面反应活性高、活动中心多、吸附能力强等特性。
6 结论与展望
通过检索、分析1993~2013年植物活性成分超临界微粉化方面的文献,发现1993~2007年间相关研究报道较少;从2008年起,文献数大幅上升,2011~2012年表现尤为活跃,表明植物活性成分的微粉化在学术界越来越受到重视;获得的微粉化植物活性成分粒径低于1 000 nm,占57%,表明超临界微粉化技术如今达到一个较精细化的水平;采用广义的SAS和RESS 2种工艺的比例分别为70.37%和29.63%,表明植物活性成分中能溶于超临界二氧化碳的数量相对较少,绝大多数活性成分需采用SAS法微粉化;植物活性单体成分占79.63%,混合物后20.37%,混合物的比例达到一个较高的水平。混合物中含有的成分较多,对粒径和含量的控制相对困难。这也是该领域研究的一个难点。但是,目前的相关文献绝大多数只限于研究阶段,主要集中在试验过程的机制、过程中的影响因素及工艺的可行性,还不能完全的进行工业化生产。试验阶段的研究工作放大到工业应用还有许多技术问题需要解决。这一问题也是超临界流体微粉化使得植物活性成分达到工业化水平的关键所在。但是,从目前的研究进展、可行性及表现的优越性来看,超临界技术在工业上实现植物活性分的微粉化具有广阔的应用前景。
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关键词 超临界流体;微粉化;植物活性成分;超临界溶液快速膨胀技术;超临界溶液反溶剂法制备技术
中图分类号 S567 文献标识码
A 文章编号 0517-6611(2014)05-01291-04
Abstract The research progress of supercritical technology in micronized plant active ingredients was reviewed, the characterization, feature and the future development prospects of micronized plant active ingredients were elaborated.
Key words Supercritical fluid; Micronization; Plant active ingredients; Rapid expansion of supercritical solution (RESS); Preparation of supercritical solution by antisolvent method (SAS)
植物成分分为初生代谢产物和次生代谢产物2种。初生代谢产物是指生物在生长过程中通过新陈代谢产生的,如α-酮戊二酸、柠檬酸、谷氨酸、丙氨酸等。次生代谢产物是指由次生代谢产生的一类细胞生命活动或植物生长发育正常运行的非必需的小分子有机化合物,如萜类、黄酮、生物碱、甾体、木质素、矿物质等。这些物质对人类以及各种生物具有生理促进作用。植物活性成分源于次生代谢产物。其种类多,用途广泛,大多数产物用于医药学领域的研究,已在世界成为一个分支领域。但是,很多次生代谢产物的水溶性都很低,颗粒较大,导致很难被人体吸收,使得植物活性成分的生物利用度降低。
1 植物活性成分的水溶性
植物活性成分分为单体和有效部位(混合物)。植物活性成分单体是指来源于植物的一种纯物质,具有某种活性,含量在98.5%以上,如喜树碱、紫杉醇、白藜芦醇等属于单体;植物活性成分的有效部位是與来源于植物的分子结构相似的一类物质,混合在一起具有某种活性,如茶叶、三七总皂苷、银杏和人参提取物等属于有效部位。植物活性成分单体应用十分广泛,而有效部位在我国早期应用很多,现已在国际上得到认可。越来越多新的植物活性成分存在水溶性差、溶解度低的缺点,在美国药典收载的药物中超过1/3的药物存在水溶性差的问题。如何提高这些植物活性化学物的水溶性和生物利用度,达到可接受的生物有效性,对医学领域无疑是一个重大的挑战[1]。
2 超临界技术微粉化的特点
基于超临界流体制备的活性成分微粉具有颗粒小、比表面积大、活性中心多、表面反应活性高、吸附能力强等特性,因此它拥有很多常规药物所不具备的作用。超临界微粉化是由晶体状态变成无定形态的过程,可提高微粉的溶解度和溶出速率。该过程是经过物理作用来实现微粉化的,不会改变药物的化学性质,所以微粉化以后的药物活性不变。药物通过微粉化以后,具有粒径十分微小的特点,可通过生物体内的大部分组织屏障,而且进入体内以后的吸收、分布、代谢和排泄循环系统都与传统药物不同。微粉化药物的这些特点可以改善某些传统药物在体内作用小、生物利用度低的缺点。
3 植物活性成分超临界微粉化的进展
为了全面了解近20年来植物活性成分超临界微粉化方面的研究现状,检索了国际权威数据库web of science中收录的文献,一共有54篇(表1)。从图1可以看出,1993~2007年间相关的研究报道较少,每年只有1~2篇;从2008年起,文献数大幅上升,在2011、2012年表现尤为活跃(2013年文献数较少,可能是web of science数据库收录滞后的原因)。这表明植物活性成分的微粉化在学术界越来越受到重视。通过将上述文献按照不同的指标进行量化,表现出以下特点。①5年文献数。图2a为1993~2013年间以5年为1个周期的文献比例图,其中1993~1997和1998~2002年的百分比分别为3.70%和1.85%,而2003~2007年上升为11.11%,2008~2013年大幅度提高,占总数的83.33%。②粒径大小。图2b为文献报道的微粉粒径情况,粒径在>1 μm、500~1 000 nm和<500 nm 3个粒径区间的百分数分别为43%、15%和42%,即粒径小于1 000 nm的合计占57%,表明超临界微粉化技术如今达到一个比较精细化的水平。③超临界微粉化工艺的类别。图2c是广义的SAS和RESS 2种工艺的比例图,百分数分别为70.37%和29.63%,表明植物活性成分中能溶于超临界二氧化碳的数量相对较少,绝大多数活性成分需采用SAS法微粉化。④植物活性成分的类别。图2d文献中报道的单体和混合物分布图,其中单体占79.63%,混合物为20.37%,混合物的比例也达到一个较高的水平。由于混合物含有的成分较多,对粒径和含量的控制相对困难,因而这也是该领域研究的一个难点。
4 微粉化植物活性成分的表征
微粉化植物活性成分的表征是非常重要的,目前主要集中在对其化学结构、物理结构、形貌和粒径、溶剂残留等方面。在化学结构测定方面,许多研究都采用傅氏转换红外线光谱分析仪(FTIR)和液相色谱质谱联用(LCMS)来检测和分析植物活性成分微粉化之后的化学结构是否发生变化。几乎所有的研究都表明,经过超临界微粉化的植物活性成分的化学结构没有发生变化。它是一种条件十分温和的微粉化技术,尤其适合具热敏性、易氧化等特性的植物活性成分。在物理结构测定方面,通常采用X射线粉末衍射(XRD)、差示扫描量热仪(DSC)和热重分析仪(TGA)等方法联用分析微粉化前后晶体结构的变化,即是否形成新的晶体或结晶度降低或形成无定形态,从而推测所得微粉化植物活性成分在溶解度、溶出速度、热稳定性等方面可能出现的特点。在形貌和粒径测定方面,随着检测设备的不断出现,微粉化活性成分的形貌的测定,也由早期的放大倍率只有1 000倍的光学显微镜逐渐发展成为扫描电镜、透射电镜来进行检测,目前还出现具有3维成像功能的原子力显微成像观测技术,可以实现在长、宽、高3个维度进行量化测定。在溶剂残留方面,将样品采用易挥发溶剂进行萃取,然后采用气相色谱法进行溶剂残留测定,超临界微粉化得到纯度高、无毒无害的微粉化植物活性成分,溶剂残留符合ICH规定的要求,表明这是一种“绿色环保”的微粉化技术。 5 微粉化植物活性成分的特點
采用超临界技术获得的植物活性成分因其在粒径、比表面积、晶体结构、表面电位等方面发生改变,在溶解度、生物利用度和活性方面也发生相应变化。①溶解度。活性成分微粉化后因其粒径降低,比表面积增加,可以提高其在生物体内的溶出速率和溶解度。这对于活性成分在体内快速起效是十分有利的。②生物利用度。采用超临界流体技术制备的微粉化植物活性成分,以大鼠为受试模型动物口服或注射给药、眼球取血、高效液相色谱仪血药浓度检测。大多数文献表明,其体内生物利用度与原粉相比有大幅度的提高。③活性。当植物活性成分颗粒达到纳米级水平时,随着颗粒总表面的增加,与胃肠道液体的有效面积明显增加,提高活性成分的溶出速率;在具有相同的药物效果前提下,可以减少药物用药量,减轻或消除植物活性成分的毒副作用;植物活性成分具有颗粒小、比表面积大、表面反应活性高、活动中心多、吸附能力强等特性。
6 结论与展望
通过检索、分析1993~2013年植物活性成分超临界微粉化方面的文献,发现1993~2007年间相关研究报道较少;从2008年起,文献数大幅上升,2011~2012年表现尤为活跃,表明植物活性成分的微粉化在学术界越来越受到重视;获得的微粉化植物活性成分粒径低于1 000 nm,占57%,表明超临界微粉化技术如今达到一个较精细化的水平;采用广义的SAS和RESS 2种工艺的比例分别为70.37%和29.63%,表明植物活性成分中能溶于超临界二氧化碳的数量相对较少,绝大多数活性成分需采用SAS法微粉化;植物活性单体成分占79.63%,混合物后20.37%,混合物的比例达到一个较高的水平。混合物中含有的成分较多,对粒径和含量的控制相对困难。这也是该领域研究的一个难点。但是,目前的相关文献绝大多数只限于研究阶段,主要集中在试验过程的机制、过程中的影响因素及工艺的可行性,还不能完全的进行工业化生产。试验阶段的研究工作放大到工业应用还有许多技术问题需要解决。这一问题也是超临界流体微粉化使得植物活性成分达到工业化水平的关键所在。但是,从目前的研究进展、可行性及表现的优越性来看,超临界技术在工业上实现植物活性分的微粉化具有广阔的应用前景。
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