【作者】 陈梅莉；

【导师】 刘龙孝；

【作者基本信息】 浙江大学 ， 药剂学， 2010， 硕士

【摘要】 目前,临床上使用的药物当中有1／3以上为难溶性药物。由于难溶性药物溶出和吸收慢,导致体内生物利用度低,影响了其在临床上的应用。因此,如何提高提高难溶性药物的溶解度和溶出度是药剂学的一个难点问题。本文将固体分散用于橙皮素,β-环糊精(β-CD)及其衍生物羟丙基β-CD (HP-β-CD)、磺丁基醚β-CD (SBE-β-CD)包合用于穿心莲内酯研究难溶性药物增溶。主要研究内容和结果如下：(1)以PVPk30和Tween80为复合载体,采用溶剂法制备橙皮素的三元固体分散体,测定其溶出度,与相应比例的橙皮素-PVPk30制成的二元固体分散体进行比较,发现由橙皮素与PVPk30和Tween80制备的三元固体分散体明显提高了橙皮素溶出度。用红外光谱法(FTIR)、差示扫描量热法(DSC)、X-射线粉末衍射法(XRD)鉴定橙皮素在三元固体分散体中的存在状态。结果表明橙皮素以非晶态分散在固体分散体中。(2)分别考察β-CD及其两种衍生物HP-β-CD、SBE-β-CD与穿心莲内酯的相溶解度,判断包合类型并计算稳定常数。研究表明：β-CD、HP-β-CD和SBE-β-CD可与穿心莲内酯形成摩尔比为1：1的包合物,其包合类型分别为Bs型、AL型和AL型,前者在高浓度的β-CD溶液中环糊精羟基间所形成的分子间氢键使穿心莲内酯难以进入孔内,从而使穿心莲内酯溶解度下降；后二者随着HP-β-CD或SBE-β-CD溶液浓度的增加,穿心莲内酯的溶解度也增加。稳定常数表明用β-CD、HP-β-CD、SBE-β-CD包合后所形成的包合物均较稳定。分别采用研磨法、超声法和共沉淀法制备穿心莲内酯的β-CD及其衍生物包合物,测定其溶出度,并与穿心莲内酯原药,以及穿心莲内酯与各种环糊精的物理混合物的溶出性能进行比较,发现包合后穿心莲内酯的溶出率显著增加。用差示扫描量热法,X-射线衍射和红外光谱对穿心莲内酯进行物相鉴别。结果表明,用研磨法、超声波法和共沉淀法制备的穿心莲内酯-p-CD体系确实形成了包合物。更多还原

【Abstract】 There are a lot of poorly water-soluble drugs in clinic. Those drugs are slowly absorbed, which lead to low bioavailability and effect their clinical application. In this paper, the solubility of poorly water-soluble drugs which was dispersed in the polymer carrier or inclused byβ-cyclodextrin (β-CD) and its two derivatives hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) was studied.The following contents were studied:(1) Ternary solid dispersions consisting of hesperetin, PVPk30 and Polysorbate 80 were prepared in various weight ratios by solvent-evaporation method. Solid dispersions of hesperetin andin PVPk30 in corresponding weight ratios were also prepared for comparison. Dissolution test was performed to investigate the pharmaceutical performance of solid dispersions.The fourier transformation-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffactionary (XRD) were used to identify the status of hesperetin in the ternary solid dispersions.(2) The phase solubility profiles of andrographolide withβ-CD, HP-β-CD and SBE-β-CD were investigated to determine the inclusion types and calculate the stability constants. It was found that the inclusion type of andrographolide withβ-CD was BS and that with HP-β-CD and SBE-β-CD were AL. The solubility of andrographolide could be lower in higher concentration ofβ-CD which might be due to a steric hindrance of hydrophilic action between (3-CDs which prevented andrographolide from entering the CD cavity. The solubility of andrographolide was markedly enhanced by either HP-(3-CD or SBE-β-CD. It could be concluded that andrographolide could form stable complexes withβ-CDs according to the stability constants.Various methods were employed to prepare the inclusion complexes of andrographolide with P-CDs. Then the dissolution profiles of the inclusion complexes were determined and compared with those of original andrographolide and physical mixtures. The results suggested that the inclusion complexes obviously enhanced the dissolution rate of andrographolide.Binary systems of andrographolide withβ-CDs prepared by various methods were characterized by DSC, XRD and FTIR. It was confirmed that the inclusion complexes of andrographolide withβ-CDs prepared by all the various methods were formed.更多还原