葛根素衍生物4ac纳米粒的制备和体内外评价
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摘要
葛根为Pueraria lobata(Willd.)Ohwi的根，一种传统的中药，首载于《神农本草经》，长期用于治疗高血压、老年性脑缺血和心绞痛等。在葛根提取物中发现四个主要的黄酮类物质，葛根素、大豆苷、染料木苷、大豆苷原。大量的药理实验结果和临床应用表明，葛根素是其中含量最高，最主要的活性成分。近年来研究结果揭示，葛根素除有能治疗心脑血管疾病外，还具有保护中枢神经作用，可提高动物的学习和记忆，并能够解酒。尽管葛根素有着较为广阔的治疗前景，由于其生物利用度比较低，在大鼠和兔子中仅有5％-6％左右，临床上主要以注射作用应用形式，在制剂中高浓度丙二醇的加入可导致不良反应。口服是一种传统的给药方式，为病人所乐于接受，并能提高病人的生活质量。
各种各样的方法被用于改善药物的生物利用度，以增加病人的依从性。为此，从一系列的葛根素衍生物中筛选出了4ac，纳米粒是一种粒径在10-1000nm的固体粒子，许多证据已表明，纳米粒可增加药物的口服生物利用度。
溶解度、油／水分配系数、解离常数等理化性质的测定有助于对化合物的化学和生物的现象的理解，如反应速度、生物活性、吸收和转运。用溶剂蒸发法制备了4ac的纳米粒，以收率、包封率、粒径为指标，通过非线性回归，采用中心复合设计法结合效应面法优选了最佳的处方和工艺。大鼠的生物利用度实验、体外释放实验和Caco-2细胞培养实验用于评价4ac和两种纳米粒的吸收和机制。结果表明，纳米粒能够提高药物的口服生物利用度，增加药物穿过Caco-2细胞渗透量，这可能是由于制备成纳米粒后，分散性的提高、与肠黏膜的相互作用亲和力增加，以及纳米粒对肠上皮细胞强的渗透性。
Pueraria lobata(Willd.) Ohwi., a traditional Chinese medicinal herb, was first described in the Chinese material medica, Shen Nong Ben Cao Jing and has been used for the treatment of hypertension, senile ischemic cerebrovasular disease and angina pectoris for a long time. Four magor isoflavones were identified in the Pueraria lobata extract and quantified-namely, puerarin, daidzin, genistin and daidzein. pharmacology and clinical applications have shown that puerarin is the most major and abundant active ingredients. In years, Researches indicated that apart from treating of cerebrovascular and cardiovascular diseases, puerarin also has neuroprotective effects and can be used for protection of learning and memory and suppression of alcohol drinking. However, in spite of the great therapeutic interest of this drug, due to its low oral bioavailability, 5—6% only in rats and rabbit, puerarin is administered intravenously as its primary form of clinical application. Howerver, propylene glycol of high concentration is added in formulation of puerarin injection, resulting in much a few side effects. Oral form is convenient and thus preferred by the patients ,which can greatly improve the quality of life of the patients.
Various techniques and methods for enhancement of oral bioavailability are proposed to improve patient compliance. For this reason, 4ac was selected from the series of derivatives of puerarin developed in our laboratory. Its oral bioavailability is markedly increased comparing with puerarin, but which still can not match clinical require. In order to overcome the difficulties as described above, improve the therapeutic efficacy and decrease its side effects, Alternative dosage forms have been suggested including incorporation of the drug into particulate carriers. Polymeric nanoparticles (NP),defined as solid particles with assize in the range of 10-1000nm, allow encapsulation of the drugs inside polymeric matrix. Nanoparticle have been proven to be an efficient approach to achieve better pharmacokinetic profiles and to increase the oral bioavailability. Most evidence suggests that the favoured site for uptake is the PP lympho-epitelial M cell. It was recently reported that particles in the
各种各样的方法被用于改善药物的生物利用度，以增加病人的依从性。为此，从一系列的葛根素衍生物中筛选出了4ac，纳米粒是一种粒径在10-1000nm的固体粒子，许多证据已表明，纳米粒可增加药物的口服生物利用度。
溶解度、油／水分配系数、解离常数等理化性质的测定有助于对化合物的化学和生物的现象的理解，如反应速度、生物活性、吸收和转运。用溶剂蒸发法制备了4ac的纳米粒，以收率、包封率、粒径为指标，通过非线性回归，采用中心复合设计法结合效应面法优选了最佳的处方和工艺。大鼠的生物利用度实验、体外释放实验和Caco-2细胞培养实验用于评价4ac和两种纳米粒的吸收和机制。结果表明，纳米粒能够提高药物的口服生物利用度，增加药物穿过Caco-2细胞渗透量，这可能是由于制备成纳米粒后，分散性的提高、与肠黏膜的相互作用亲和力增加，以及纳米粒对肠上皮细胞强的渗透性。
Pueraria lobata(Willd.) Ohwi., a traditional Chinese medicinal herb, was first described in the Chinese material medica, Shen Nong Ben Cao Jing and has been used for the treatment of hypertension, senile ischemic cerebrovasular disease and angina pectoris for a long time. Four magor isoflavones were identified in the Pueraria lobata extract and quantified-namely, puerarin, daidzin, genistin and daidzein. pharmacology and clinical applications have shown that puerarin is the most major and abundant active ingredients. In years, Researches indicated that apart from treating of cerebrovascular and cardiovascular diseases, puerarin also has neuroprotective effects and can be used for protection of learning and memory and suppression of alcohol drinking. However, in spite of the great therapeutic interest of this drug, due to its low oral bioavailability, 5—6% only in rats and rabbit, puerarin is administered intravenously as its primary form of clinical application. Howerver, propylene glycol of high concentration is added in formulation of puerarin injection, resulting in much a few side effects. Oral form is convenient and thus preferred by the patients ,which can greatly improve the quality of life of the patients.
Various techniques and methods for enhancement of oral bioavailability are proposed to improve patient compliance. For this reason, 4ac was selected from the series of derivatives of puerarin developed in our laboratory. Its oral bioavailability is markedly increased comparing with puerarin, but which still can not match clinical require. In order to overcome the difficulties as described above, improve the therapeutic efficacy and decrease its side effects, Alternative dosage forms have been suggested including incorporation of the drug into particulate carriers. Polymeric nanoparticles (NP),defined as solid particles with assize in the range of 10-1000nm, allow encapsulation of the drugs inside polymeric matrix. Nanoparticle have been proven to be an efficient approach to achieve better pharmacokinetic profiles and to increase the oral bioavailability. Most evidence suggests that the favoured site for uptake is the PP lympho-epitelial M cell. It was recently reported that particles in the
引文
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