中药微乳载药体系关键技术研究

【作者】 杜红；

【导师】 牛欣；

【作者基本信息】 北京中医药大学 ， 中西医结合基础， 2008， 博士

【摘要】 微乳是近年兴起的新型载药体系。微乳结构是热力学稳定的油-水-表面活性剂-助表面活性剂的均相体系,外观透明或近似透明,也同一般乳剂一样分为W/O和O/W型,粒径小,通常在10-100nm之间,所以也称之为纳米乳。微乳液与普通乳液不同,它在外观上呈透明或者半透明状,粘度远小于乳液而接近于水,其最大的特点是微乳液粒径远远小于普通乳液,在10-100nm之间,且均匀分布,热力学稳定,而普通乳状液粒径在100nm以上,分布不均匀,长期放置或离心会发生分层。微乳液也不同于胶团溶液,胶团溶液的分散相含量较小,而微乳液分散相含量远远高于胶团溶液。正是由于这些特点,微乳作为药物载体的应用逐渐引起人们的重视。微乳作为一种新型药物载体,具有极大的应用潜力。主要具有以下几个优点:⑴微乳制剂可以提高难溶性药物的溶解度,大大减少此类药物的服用量。⑵微乳制剂粒径小,可以有效、快速的通过胃肠道上皮细胞,大大提高药物的生物利用度。⑶微乳制剂可以制成多种剂型,包括口服制剂,注射制剂和透皮吸收制剂。⑷其处方一经确定,制备方法简单。本研究目的在于探讨微乳载药体系在中药领域中应用的关键问题,为中药微乳制剂的广泛应用奠定基础。研究内容有以下四篇:1.中药微乳制剂制备关键技术研究本篇分别从单个有效成分、有效成分组方、单味中药、中药复方四个方面进行了中药微乳制剂制备技术的研究。微乳制备的关键问题是配方的筛选过程,选择合适的工具和方法可以使筛选配方的过程简化。本文采用滴定法,辅以自主设计的相图绘制计算机软件(MEPDplot)进行配方筛选,实验证实该法简单易行,所得相图接近真实情况,可大大降低配方筛选的工作量;对于中药有效成分及复方的微乳制备,关键的问题是选择合适的四相,要求辅料用量尽可能少,对主药的增溶作用尽可能大;对于“整体”单味中药及其复方微乳,适用于含挥发油较多的药物,其制备的关键问题一方面是要选择合适的提取和纯化水溶性成分和油性成分的方法,另一方面要选择合适的表面活性剂和助表面活性剂,使其恰好能够与中药中提取的油和水能形成微乳。此外,本篇还提出了微乳提取技术制备中药微乳的方法,该方法的核心问题除了选择合适的微乳配方以外,还要寻找有效的提取方法,该方法一经确立,提取的过程即为制剂过程,且适用性广,大大降低了成本,并扩大了微乳载药体系的应用范围。2.微乳制剂质量标准的制定本篇以穿心莲内酯微乳为例,参考中华人民共和国药典中口服液和乳剂的质量标准,制定了微乳制剂的相关质量标准。质量标准草案内容包括:名称、处方、制法、性状、鉴别、检查、含量测定、功能主治、用法用量、规格、贮藏、有效期。检查项下内容包括装量、相对密度、PH值、动力学检查、含量测定、微生物限度检查。质量标准起草说明中除上述项外,还包括微乳粒径及形态的考察。3.中药微乳制剂药效、生物利用度比较研究本篇选取穿心莲内酯微乳、川芎微乳、穿心莲微乳提取液为研究对象,从中药有效成分微乳、“整体”中药微乳、中药微乳提取三方面对中药微乳制剂的药效和相对生物利用度进行研究。实验中分别选取与上述三种药物同种其他剂型药物作为对照进行比较研究,研究结果显示微乳制剂可以不同程度的增强药效并提高生物利用度。4.微乳制剂吸收机制探讨本篇以穿心莲内酯微乳为代表,利用大鼠原位灌注模型考察微乳制剂的吸收机理。考察了制剂因素(PH值、浓度)对微乳吸收的影响;微乳在胃及不同肠段的吸收情况;载体抑制剂、P-糖蛋白抑制剂、能量抑制剂对微乳吸收的影响。实验结果显示,穿心莲内酯微乳在胃部的吸收良好;在小肠的吸收与药物的PH值有关,酸性药物的吸收优于中、碱性药物;随着药物浓度的增加,微乳的吸收有一定的饱和性;微乳的最佳吸收部位在小肠的中、后段,依次为回肠、空肠、十二指肠;其吸收作用需要载体;受到P-糖蛋白外排作用的影响;可能不耗能;吸收呈现明显双峰。推断出微乳吸收方式主要有两种:一种为被动跨膜转运,在胃和小肠都存在,在胃中吸收较好是微乳吸收峰提前的主要原因。可能是微乳表面张力低,粒径小,容易通过胃肠道上皮,且可以将药物包裹与乳滴当中,从而抑制药物被胃肠液的理化环境和酶的破坏;另一种方式为以颗粒的形式通过淋巴胞饮吸收,主要出现在小肠中、后段含PP丰富的区域,此种吸收造成微乳出现第二次吸收高峰,是微乳制剂生物利用度较高的主要原因。更多还原

【Abstract】 Mecroemulsion is a new drug delivery system which emerges recently. Mecroemulsion is a thermodynamics resistant homogeneous phase system which is composed of oil-water-sufactant-consurfactant, it is transparent or similar transparent in appearance, also, this system has two forma-- water-in-oil and oil-in-water, which is the same with normal emulsion, but microemulsion’s particle diameter is small which is between 10nm and 100nm, therefore, it is also named nanoemulsion. Microemulsion is different from emulsion, it is transparent in appearance, small in particle diameter, low in viscosity, stable in thermodynamics. Contrast to microemulsion, emulsion’s particle diameter is always larger than 100nm, and it will be layering after long time place or centrifugate. Microemulsion is also different from glue ball, the latter is outclass than the former in the content of disperse phase. Exactly because of these characteristic, people think highly of microemulsion as a drug delivery. Microemulsion has tremendous applying potency as a new drug delivery which has the following advantage.(1) Microemulsion can elevate the solubility of insoluvility drug and decrease the dosage of this kind drug.(2) Microemulsion has small particle diameter, because of this, it can pass gastrointestinal tract epithelial cells effetely and rapidly, improve the drug’s bioavailability.(3) Microemulsion is suit for many routes of administration, such as oral drug administration, injettion and cutaneous drug administration.(4) The method to preparation is simple once the formula is determined.The purpose of this research is to investigate the key problems of microemulsion applying in Chinese herbal drugs, and settle the basic skills for the applying of mecroemulsion generally. The contents of this research compose the following four chapters.1. The key skills in preparation of mecroemulsionThis chapter researches the key skills to prepare Chinese herbal drug microemulsion in four aspects: single active component, active component formula, single Chinese herbal drug and compound recipe. The most important point is the course of formula bolting, suitable tools and methods can simplified this process. This article use titration assisted by computer software(MEPDplot) which is designed independently to bolting formula, it has been proofed that this method is easy to do and can get the phase diagram access to the real situation, it also can cut down the workload in formula bolting. When prepare the active component and recipe microemulsion, the most important point is to select suitable phases, it has been desired few usage of adjuvant and great solubilization to main drug as far as possible. When to prepare single Chinese herbal drug and recipe microemulsion, on one hand is to select suitable method to extract and depurate the water solubility and oil, on the other hand is to select suitable surfactant and cosurfactant, which desired these two can assist the extracted water solubility and oil from Chinese herbal drug to form microemulsion. In addition, this chapter also raises a method of microemulsion extraction, in this method, the key skills also compose searching effective extract method besides the formula bolting. Once this method is determined, the process of extract is also the process of preparation, also, this method has a broad applicability, can lower the cost, enlarge the application scope of microemulsion drug delivery.2. The enact of quality standard of microemulsionThis chapter takes andrographolide mecroemulsion as example, reference emulsion and oral liquid quality standard in the Pharmacopoeia of the People’s Republic of China, enact the correlated quality standard of microemulsion. The contents of protocol include name, prescription, method of preparation, characteristics, diagnosis, check, assaying, functions and indication, directions and dosage, specification, storage and expiration date. The check item includes the dose, relative density, PH value, dynamics check, assaying and microbial limit check. The draft account of the standard also includes the shape and particle diameter check of microemulsion.3. The comparative study of potency and bioavailability of Chinese herbal drug microemulsionThis chapter select andrographolide microemulsion, Rhizoma Chanxiong microemulsion, Herba Andrographitis Paniculatae microemulsion extract liquid as study object, researches the potency and bioavailability of microemulsion drug delivery from tree aspects which are active component,‘whole’Chinese herb drug and microemulsion extract. In the experiments, three other dosage forms of the above-mentioned drug has been selected as comparative study, the findings display that microemulsion can enhance the potency and increase the bioavailability in different degree.4. The investigate of absorption mechanism of microemulsionThis chapter has select andrographolide microemulsion as example, utilize in situ perfusion model in rats to investigate the mechanism of absorption of microemulsion. In the experiment, inspect the influence of preparation factors (PH value, concentration) to absorption, the absorption information in stomach and different pare of intestine, the influence of carrier inhibitor, P-glycoprotein inhibitor, energy inhibitor to absorption. The experimental results display that, andrographolide microemulsion is absorbed well in stomach; it’s absorption in intestine concerns with the drug’s PH value, acidity drug is absorbed better than neutral and basis drug; the aborption of microemulsion show statuavility as the increase of the drug concentration; the best part to absorption is the middle and back end of intestine, one by one is ileum, jejunum, duodenum; the course of absorption needs carrier and is influenced by the excretion of P-glycoprotein, the absorption use no energy possibly; The absorption curve show obviously doublet. From the experimental results, it can be concluded that there are two main absorption pattern in the absorption course of microemulsion: the first one is passive transmembrane transport, this way exists both in stomach and intestine, it is absorbed well in stomach may be the main reason to show advanced absorption. Possibly because that microemulsion has a low surcace tension and small particle diameter, can easily transport the gastrointestinal tract epithelial cells, furthermore, in microemulsion system, the drug is packaged in milk drop, which can protect drug from the destroy of physical- chemistry factors and enzymatic in gastrointestinal tract; another absorption pattern is pinocytosised trough lymph, which mainly shown in the area where is full of PP, this may be the reason to show the second peak, is the important cause to raise the bioavailability of microemulsion.更多还原