离子液体溶剂体系下几种典型难溶性植物活性成分的反溶剂纳米结晶行为

Poorly water-soluble active ingredients from plant are strictly limited to clinical application owing to the low bioavailibility and slow dissolution rate. In recent years, antisolvent nanocrystallization (antisolvent precipitation) has been developed into an effective method to improve the bioavailibity of poorly water-soluble active ingredients from plant, which has been reported in many researches. Ionic liquid (IL) has unique physical properties including viscosity, polarity, diffusion coefficient and surface tension compared with molecular solvent, which are the key roles in the process of antisolvent nanocrystallization. IL has the ability to regulate behavior of antisolvent nanocrystallization in theory.Up to now, there is a few reports just about preparation of nanoparticles using IL as antisolvent with the help of antisolvent nanocrystallization method and the behavior and system of nanocrystallization hasn't yet been explored. For these reasons, three poorly water-soluble active ingredients including paclitaxel, camptothecin and dihydroquercetin are chosen as model compounds and attempted to be prepared into nanoparticles using antisolvent precipitation technique in ionic liquid system (ILS) in this project. The actingl law of IL on physical characters of antisolvent system and supersaturation solubility are thoroughly analysed. It is gradual to derive a quantitative relationship between physical properties of solvent and partcle size, morphology and crystal form of antisolvent nanocrystals. The mechanism of antisolvent nanocrystallization of typical active ingredients from plant in ILS is revealed and the effective regulation on antisolvent nanocrystallization behavior will be realized.

难溶植物活性成分因其生物利用度低、溶出速率慢，严重限制了它们的临床应用。反溶剂纳米结晶（或反溶剂沉淀）是近年来发展起来提高难溶活性成分生物利用度的一个有效途径，已经有不少文献报道。离子液体有区别分子溶剂的粘度、表面张力、密度等物理特性，这些物理特性均是影响反溶剂纳米结晶过程的关键参量，理论上可以运用离子液体来调控反溶剂结晶行为。目前有文献报道了用离子液体为溶剂以反溶剂结晶法制备药物纳米粒，但未对其结晶行为和机制进行研究。基于上述原因，本项目选择三种难溶性植物活性成分紫杉醇、喜树碱和二氢槲皮素为模型化合物，尝试采用离子液体溶剂体系下的反溶剂沉淀技术将其制备成纳米粒，探索离子液体对反溶剂体系的物理特性的作用规律及对过饱和度的影响，建立溶剂物理特性与反溶剂纳米结晶的粒度、形态、晶型的量化关系，揭示离子液体体系下典型植物活性成分反溶剂纳米结晶的机理，实现对其反溶剂纳米结晶行为的有效调控。

本项目以三种难溶性植物活性成分为模型化合物，采用离子液体溶剂体系下的反溶剂沉淀技术将其制备成结晶，揭示离子液体体系下活性成分结晶的机理，并进行生物学效应的初步验证，为离子液体体系下反溶剂可控结晶难溶性植物活性成分制备技术提供理论支撑。 .本研究的主要内容及获得研究结果如下：.1.确定了以离子液体1-丁基-3-甲基咪唑四氟硼酸盐作为溶剂，二氯甲烷作为反溶剂进行重结晶可以获得一种二氢槲皮素新晶型。各结晶条件不影响获得晶体的晶型，但二氢槲皮素的浓度和反溶剂/溶剂体积比对得率具有一定的影响；新晶型最高得率为71.6 %；新晶型呈较规则的倒三角锥形，原粉多呈六面体型；新晶型化学结构与原粉完全一致；新晶型X-ray衍射峰、Raman光谱和ssNMR图谱特征峰明显区别于原粉；新晶型熔点降低；新晶型的抗氧化能力要明显高于原粉；在人工胃液中新晶型的溶出速率显著快于原粉；新晶型的生物利用度是原粉的1.49倍。.2. 结晶条件与离子液体种类均影响紫杉醇晶型；溴化1己基3甲基咪唑（[HMIm]Br）为可制备水溶性紫杉醇新晶型；最佳制备条件为紫杉醇-[HMIm]Br浓度为50 mg/mL，结晶温度25 ℃和溶剂与反溶剂比1：7；新晶型在水中溶解度为6.05 µg/mL，是原粉5.6倍，生物利用度是原粉的10.88倍；新晶型的化学结构与原粉一致，形貌发生较大变化；晶体结构发生显著改变，熔点降低，推测其原因可能是碳骨架中C16-C17键角发生改变，从而使整个晶体结构蓬松，蓬松的晶体结构让水分子更容易与羟基接触，从而提高了紫杉醇的水溶性。.3. 在常用的可以溶解喜树碱的离子液体中，通过与分子液体进行反溶剂结晶，得到结晶均接近无定形态，未获得新晶型。.综上，离子液体参与条件下的反溶剂重结晶可较大概率获得难溶性植物活性成分的水溶性新晶型，显著提高其溶解度和溶出度，进而提高其口服生物利用度，为解决难溶活性成分的生物利用度低下问题提供一条新途径。