【作者】 易涛；

【导师】 杨祥良；

【作者基本信息】 华中科技大学 ， 生物化学与分子生物学， 2008， 博士

【摘要】 自微乳化给药系统(SMEDDS)能够显著提高水难溶性药物的口服生物利用度,是很有发展前途的载药系统,近年来得到越来越多的关注。但它一般是液体剂型,封装在软胶囊或硬胶囊中,因而带来生产过程复杂、成本较高、制剂成分与胶囊壳的相容性、长期储存中可能发生胶囊泄露以及剂型单一等缺点。为克服这些缺点,并整合SMEDDS和固体制剂的双重优点,固体自微乳化给药系统(S-SMEDDS)的研究开始萌芽。S-SMEDDS的固体载体、制备方法、微观结构、释药机理和体内行为是需要研究的重要问题,其中S-SMEDDS是否能保持液体SMEDDS(L-SMEDDS)原有的体内外优点是最关键的问题。围绕以上问题,本文以水溶性辅料为固体载体,采用喷雾干燥法和离子凝胶化法制备了具有不同释药特征的S-SMEDDS,完成的主要研究工作有:(1)首先研究水溶性辅料对L-SMEDDS的微观结构和载药能力的影响。以尼莫地平为模型药,制备和表征L-SMEDDS;采用电导率法和体外分散试验来研究右旋糖酐40、麦芽糖糊精、阿拉伯胶、聚乙烯吡咯烷酮K30和羟丙甲基纤维素(HPMC)等各种水溶性辅料的影响。结果表明这些水溶性辅料对L-SMEDDS的微观结构没有明显影响,却能显著增强L-SMEDDS的载药能力,抑制体外分散时药物的沉淀,可以作为制备S-SMEDDS的固体载体。(2)速释S-SMEDDS的体内外研究。选择多种水溶性辅料作为固体载体,采用喷雾干燥法制备尼莫地平速释S-SMEDDS。通过透射电镜(TEM)、扫描电镜(SEM)、差热扫描量热分析(DSC)、粉末X-射线衍射分析(PXRD)和体外溶出试验研究固体载体对S-SMEDDS外观、重分散性、药物的物理状态等性质的影响。其中以右旋糖酐40为载体的S-SMEDDS,由分离良好的球形颗粒组成,药物以无定形或分子分散状态存在,水重分散后形成粒径小于50nm的微乳,体外溶出快速,显著高于市售片剂。兔口服生物利用度研究结果显示,在禁食和进食两种条件下,以右旋糖酐40为载体的S-SMEDDS的AUC0→12h分别是片剂的2.5倍和2.6倍,Cmax分别是片剂的6.6倍和5.8倍;但和L-SMEDDS比较,没有统计学上的显著性差异。以上结果说明S-SMEDDS能够保持L-SMEDDS的体内外优点。(3)在速释S-SMEDDS体内外研究的基础上,进一步研究缓释S-SMEDDS。以高粘度级别的HPMC为固体载体,采用喷雾干燥法制备尼莫地平的自微乳化缓释颗粒,并同法制备相应的非自微乳化缓释颗粒作为参比制剂。TEM结果显示缓释S-SMEDDS遇水重分散后能形成粒径小于100nm的微乳;在SEM、DSC和PXRD分析结果基础上,提出缓释自微乳化HPMC颗粒和非自微乳化HPMC颗粒的微观结构假设,推测两者的结构差异可能会导致体外释药行为的改变。应用零级动力学模型、Hixson-Crowell模型、Higuchi模型和经验公式power law对两类制剂的体外释药数据进行模型拟合。结果表明两者释药机制不同,扩散机制在缓释S-SMEDDS的体外释药行为中起到相对更加重要的作用。这也验证了HPMC颗粒结构假设的合理性。(4)为扩大SMEDSS的药物适用范围,对肠溶S-SMEDDS进行了初步研究。以吲哚美辛为模型药,采用离子凝胶化法制备肠溶自微乳化胶珠。重分散性试验结果表明肠溶自微乳化胶珠能在人工肠液中形成粒径小于150nm的微乳;SEM结果显示胶珠为表面致密、内部疏松的球形;DSC和PXRD分析结果表明药物在胶珠中为无定形状态。采用相似因子法和模型拟合对体外释药行为的处方影响因素和释药机理进行初步探讨,结果显示肠溶自微乳化胶珠的体外释药行为主要受液体自微乳与海藻酸钠的质量比、海藻酸钠浓度的影响,载体的溶蚀可能是主要的释药机制。本文研究建立了具有不同释药特征的S-SMEDDS,能够保持L-SMEDDS的体内外优点,既丰富了SMEDDS的固体剂型,又扩大了药物适用范围,为S-SMEDDS的研究发展提供了新思路、新方法。在本文对S-SMEDSS的固体载体、微观结构、释药机理和体内行为的初步研究基础上,有必要通过进一步研究固体载体的分子量、粘度等性质的影响和S-SMEDDSS的体内吸收行为,建立新的释药动力学模型和体内外相关性,为指导S-SMEDDS的处方筛选和体内外评价提供基础。更多还原

【Abstract】 In recent years, increasing attention has been focused on self-microemulsifying drug delivery system (SMEDDS), which has shown a great success in improving oral bioavailability of poorly soluble drugs and becomes a potential drug delivery system. Conventionally, SMEDDS is prepared as liquid dosage forms that can be encapsulated in hard or soft gelatin capsules, which has some shortcomings especially in the manufacturing process, leading to high production costs. Moreover, these dosage forms may be prone to leakage during shelf-life, and incompatibility problems with the shells of the soft gelatin are usual. In order to overcome the shortcomings of liquid formulations and to combine the advantages of SMEDDS with those of solid dosage forms, studies on solid self-microemulsifying drug delivery system (S-SMEDDS) have begun.Solid carriers, preparation method, microstructure, drug release mechanism and in vivo absorption are important aspects of S-SMEDDS. It is the key issue that whether S-SMEDDS could maintain the in vitro and in vivo characteristics of L-SMEDDS. In this dissertation, S-SMEDDS with various drug release patterns were prepared by spray-drying or ion gelation, using water soluble excipients as solid carriers.(1) L-SMEDDS was prepared and characterized using nimodipine as a model drug. The effects of various water soluble carriers on internal microstructure and solubilization of L-SMEDDS were investigated by conductivity and in vitro dispersion. The results showed that water soluble carriers did not seem to have a remarkable effect on microstructure of L-SMEDDS. However, the water soluble carriers had increased solubilization of nimodipine in the self-microemulsifying system and decreased drug precipitation when dispersed in aqueous media.(2) S-SMEDDS of nimodipine were prepared by spray drying with water-soluble solid carriers. The effects of various water soluble carriers on the properties of S-SMEDDS were investigated by TEM, SEM, DSC, PXRD and in vitro dissolution. The results shown that solid carriers, especially the molecular weight of carrier, had an obvious influence on the surface morphologies of S-SMEDDS, reconstitution of microemulsion and the physical state of nimodipine in S-SMEDDS. The S-SMEDDS with dextran 40 as solid carrier, consisted of well-separated spherical particles and could form microemulsion with droplet size less than 50nm followed by dilution in water. Nimodipine in the S-SMEDDS was in the amorphous or molecular dispersion state. The S-SMEDDS had a faster in vitro release rate than the conventional tablet.(3) A comparative bioavailability study was performed in rabbits with the solid SMEDDS, the liquid SMEDDS and a conventional tablet of nimodipine. In fasted and fed conditions, the areas under the curves (AUC0→12h) for the S-SMEDDS were 2.5 and 2.6 times greater, respectively, and the mean values of Cmax for the S-SMEDDS were 6.6 and 5.5 times greater, respectively, compared to the conventional tablet. However, both AUC0→12h and Cmax for the S-SMEDDS and L-SMEDDS were not statistically different (p > 0.05). It suggested that the S-SMEDDS maintained the absorption characteristics of the L-SMEDDS.(4) HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system. TEM micrograph revealed that the reconstituted microemulsions with droplet size less than 100nm were released from the S-SMEDDS when exposed to aqueous media. Based on investigation by TEM, SEM, DSC and X-ray powder diffraction, differences were found in the particle structure between both types of formulations and potential structures were supposed. Dissolution data of both formulations were fitted to various mathematical models in order to describe the release kinetics. It was found that diffusion was the comparatively important drug release mechanism of the controlled release S-SMEDDS, differed from the controlled release formulation without self-microemulsifying ingredients. The differences in the particle structure could be an explanation for the difference in drug release mechanism.(5) Self-microemulsifying enteric gel beads (SMEGB) were prepared by ion gelation, using indomethacin as a model drug. Reconstitution test results showed that the reconstituted microemulsion with droplet size less than 150nm was released from SMEGB when exposed to aqueous media. SEM micrographs illustrated that the gel bead showed a regular spherical shape, with more compact surface and looser internal structure. Indomethacin in the SMEGB was in the amorphous or molecular dispersion state. The influence factors and drug release mechanisms were preliminarily investigated by the similarity factor and model fitting. It was found that the main influence factors were the mass ratio of L-SMEDDS/sodium alginate and the concentration of sodium alginate. It was possible that erosion of carrier was the main drug release mechanisms of SMEGB.In present work, S-SMEDDS with various drug release patterns were successfully prepared, maintaining the in vitro and in vivo characteristics of L-SMEDDS. Effects of water soluble carriers, changes of microstructure, drug release mechanisms and in vivo absorptions of S-SMEDDS were also preliminarily investigated. In the future, further investigations are necessary to establish new model of drug release and in vitro and in vivo correlation, providing an important base on S-SMEDDS formulation strategy and in vitro and in vivo assessment.更多还原