【作者】 李丽；

【导师】 高申；

【作者基本信息】 第二军医大学 ， 药剂学， 2008， 硕士

【摘要】 提高难溶性药物生物利用度是一直以来药剂学面临的问题。自微乳化给药体系(SMEDDS)是由药物、油相、表面活性剂和辅助表面活性剂组成的均一、透明的溶液,在特定温度和温和搅拌的条件下,遇水自发乳化形成粒子在150nm以下的乳剂。与常规乳剂相比,微乳是一种热力学稳定体系,具有更高的分散度(通常在10～140nm之间),并且由于一些特殊表面活性剂的作用,自微乳化给药体系(SMEDDS)可以通过多种渠道达到提高药物生物利用度的目的。研发难溶性药物的自微乳化给药体系的关键在于发现合适的药物载体(油相、表面活性剂、助表面活性剂以及适当的增溶剂)。因此,对于材料的了解和筛选显得尤为重要。自微乳化给药体系(SMEDDS)主要研发手段是采用伪三元相图以及对微乳的理化性质分析。其中着重要考虑的因素有载体对药物的溶解能力、自微乳化体系在伪三元相图区域特点、形成微乳后药物的溶出度和微乳粒径的大小。这些都是影响药物生物利用度的重要因素。本课题以难溶性药物吡罗昔康为模型药物,吡罗昔康(Piroxicam)又名炎痛昔康,是辉瑞公司研发出来的解热镇痛类非甾体抗炎药,文献报道,吡罗昔康难溶于水、生物利用度低。本课题对吡罗昔康自微乳化给药体系(SMEDDS)进行了探索性研究,本研究建立了高效液相色谱法梯度洗脱测定吡罗昔康含量的方法:对15种常用自微乳化辅料进行了筛选,优选出以辛酸甘油酯为油相、月桂酸聚乙二醇甘油酯为乳化剂、二乙二醇单乙基醚为助表面活性剂的吡罗昔康自微乳化给药系统,并对其进行了体内外评价。体外溶出结果表明,5min内药物的溶出大于80%,平均粒径在33nm左右;在以吡罗昔康Tmax未发生明显改变,Cmax提高4.8倍。相对生物利用度为466%.更多还原

【Abstract】 The enhancement of oral bioavailability of poorly water soluble active pharmaceutical ingredients (APIs) or new chemical entities (NCEs) remains one of the most challenging aspects of drug development. Although salt formation, solid dispersion, cyclodextrin inclusion, liposome, solubilisation and micronization have commonly been used to enhance the in vitro dissolution rate and thereby oral absorption and bioavailability, there are practical difficulties. The use of very fine powders may still be problematic to handle due to poor wettability. Lipid-based drug delivery systems have gained an important place in the formulation of poorly soluble drugs for oral administration. Lipid-based formulations are typically administered in liquid form, generally in soft-gel capsules. This can offer favorable dissolution, release, and bioavailability properties. Self emulsifying drug deliver system (SEDDS) and self micro-emulsifying drug deliver system (SMEDDS) is one of the technologies to improve poorly water soluble APIs or NCEs wettability, dissolution rate, bioavailability.There are a number of characteristics of lipid-based delivery systems which make them an important tool to formulate drugs with dissolution-rate limited absorption. Advantages include solubilisation of hydrophobic drugs in the lipid matrix, absorption enhancement, and avoidance of the food effect. Components of these formulations include triglycerides, which can be long chain (14-18 carbons), or medium chain (6-12). The latter are less viscous and generally have higher solubilisation ability than long chain analogues. Mono-/diglycerides are more hydrophilic than corresponding triglycerides, and have higher solubilisation ability and dispersibility. Fatty acids (e.g. oleic acid), co-solvents, and surfactants may also be important components of lipid-based formulations. Surfactants can be categorised into either high hydrophilic-lipophilic balance (HLB), such as polysorbates, polyoxyl castor oils (Cremophor(?)), Gelucire(?) 44/14, Labrasol(?), poloxamers, and Vitamin E TPGS, or low HLB (e.g. SPAN(?), Labrafil(?), lecithins); both high and low HLB surfactants are useful in formulating lipid-based drug delivery systems. When added to water, those with higher levels of surfactants and co-solvents will disperse into smaller droplet size, which will aid absorption of drugs in the intestinal lumen due to the larger available droplet surface area. Nevertheless, even those lipid formulations with low surfactant and cosolvent content (and thus relatively large initial droplet size after dispersion) will often afford adequate absorption of poorly soluble drugs. This is due to the fact that in the gastrointestinal (GI) tract, triglycerides will be digested by lipases into mono- and di-glycerides, glycerol, and fatty acids, which will themselves act as surfactants and reduce the particle size. These will be further solubilised by bile salts and phospholipids to form mixed micelles of low particle size, favoring partitioning and diffusion of drug molecules to the surface of the enterocytes for absorption. The process of digestion is crucial for drug absorption for lipid formulations with low surfactant content, while those with high surfactant and co-solvent content will have less dependence on digestion products for their emulsification. A useful tool for understanding the phase structure and properties of lipid-based drug delivery systems is the phase diagram . The types of structures formed can be identified as a function of oil/surfactant/water ratios. This will aid in understanding changes encountered over the dilution path, and thus serve as a tool for choosing the formulation composition .This paper presents the use of vehicle/excipient screening for judicious selection of type and concentration of each excipient in formulating a SMEDDS of a poorly soluble drug (Piroxicam). This paper will outline the general concepts of solubilisation and bioavailability enhancement with lipid-based formulations; compare liquid and solid dosage forms. Finally, chemical and physical stability considerations for lipid-based drug delivery systems will be discussed. The pros and cons of the various approaches for lipid-based formulations will be outlined in order to guide the formulator in choosing an appropriate dosage form based on drug profile and application requirements. The dissolution rate and particle size of Piroxicam SMEDDS was evaluated in vitro. The bioavailability of Piroxicam SMEDDS in rabbit showed 4.8 times Cmax and 466% bioavailability compared with suspention dosage form.更多还原