【作者】 张熙；

【导师】 吴伟；

【作者基本信息】 复旦大学 ， 药剂学， 2012， 硕士

【摘要】 自微乳化给药系统(SMEDDS)能够显著提高难溶性药物的溶解度,促进经口服吸收,因而可以显著提高其生物利用度。然而,SMEDDS经口服后吸收速率较快,导致达峰时间短,峰谷波动大。为克服SMEDDS吸收过快的问题,本文拟设计基于渗透泵原理的SMEDDS控释片,以期达到控制微乳滴释放、平稳血药浓度、减少给药次数的目的。本文提出了将微乳滴作为整体控制释放的概念,以环孢素A为模型药物,主要研究了各种影响因素对其释放的影响,并在Beagle犬体内验证其控制释放效果。控释体系设计为自微乳渗透泵片(self-micro-emulsifying osmotic pump tablet, SMEOPT),通过控制微乳滴的释放而达到药物的控制释放,其优势有：①通过做成纳米粒,可改善难溶性药物的溶解度,并提高体内生物利用度；②再通过对纳米粒的控制释放达到对难溶性药物的控制释放,从而减少给药次数和提高患者依从性。第一章建立了环孢素A、非诺贝特、非洛地平的体外分析方法,其中包括释放试验测定的分析方法和含量测定试验的分析方法。经专属性、精密度、准确度考察,本文所建立的分析方法符合要求。第二章中制备了SMEOPT,并对影响药物释放的因素进行了系统的考察。SMEOPT的具体制备方法是：先用Labrafil M1944CS、Transcutol P和CremophorEL做成自微乳化给药系统,再与蔗糖、乳糖、PEO和预胶化淀粉混合压制成片,最后以醋酸纤维素为成膜材料、PEG4000为致孔剂进行包衣。包衣均匀度考察表明包衣增重为2%时的RSD为6.24%,包衣膜均匀。微乳滴的释放行为通过检测环孢素A来考察。本文考察了影响微乳滴释放的多种因素,包括渗透活性物质种类、渗透活性物质与PEO的比例、包衣膜重量、致孔剂含量和释药孔大小。通过透射电子显微镜观察和粒径测定,证实从SMEOPT中再分散形成的微乳滴与从SMEDDS中分散形成的微乳滴在大小和形态上无明显差别。另外,本文验证了SMEOPT对微乳滴的控制释放行为与普通单室渗透泵片对药物分子的控制释放作用相似。总的来说,在影响微乳滴的释放因素中,与释放速率成正比的是渗透压的大小、渗透活性物质与PEO的比例、致孔剂含量和释药孔大小,与释放速率成反比的是包衣膜厚度。第三章中对SMEOPT的药动学在Beagle犬体内进行了考察。结果表明SMEOPT (AUC=805.4±181.0ng/L·h)和片芯(AUC=849.8±158.1ng/L-h)相对于市售环孢素A软胶囊Sandimmun Neoral(?)(AUC=732.3±177.4ng/L·h)的相对口服生物利用度分别为110%和116.1%,三者之间无显著性差异。SMEOPT (MRT(0-∞)=12.0±2.1h)与片芯(MRT(0-∞)=8.6±1.4h)和市售Sandimmun Neoral(?)(MRT(0-∞)=8.0±1.1h)相比,体内滞留时间显著延长。本文基于渗透泵控释原理,初步验证了以微乳滴作为整体释放的学术观点,药物的释放与微乳滴的释放同步,与药物本身的性质无关。更多还原

【Abstract】 Self-microemulsifying drug delivery system (SMDDS) can significantly enhance solubility of insoluble drugs and improve oral absorption, thus advance bioavailability a lot. However, SMDDS can be absorbed so quickly that it leads to a small Cmax and big fluctuation of blood concentration. In order to solve the problem of quick absorption, this paper aims to design a controlled release system of SMEDDS basing on osmotic pump tablet. This paper firstly advanced the concept of controlled release of intact nanoparticles. In this study, microemulsion droplet was used as model nanoparticle and osmotic pump tablet was employed as control release system to make self-microemulsion osmotic pump tablet (SMEOPT). Cyclosporine A was used as model drug and mainly investigated various factors’ effect on the release behavior of micro-emulsion droplets. In vivo pharmacokinetics of the drug delivery system was also tested. SMEOPT has two characters:firstly, it can improve solubility and bioavailability of insoluble drug by making them into liponanoparticles; secondly, SMEOPT can realize controlling of insoluble drugs which decrease administration times and increase compliance.In vitro analytic methods of cyclosporine A, fenofibrate and felodipine were constructed. These methods were validated by specificity, precision and recovery test.Self-microemulsifying drug delivery system (SMEDDS) consisting of Labrafil M1944CS, Transcutol P and Cremophor EL was mixed with sucrose, lactose monohydrate, poly(ethylene oxide), and partly pregelatinized starch and then transformed to tablet cores by a single punch tablet press. The tablet cores were finally coated by semipermeable membrane (cellulose acetate) through pan coating process. Release of microemulsion droplets was characterized by determination of enclosed drug molecules. Various factors affecting release of microemulsion were explored, including osmotic active substances, coating weight gain, content of pore maker and size of release orifice. Our study suggested the microemulsion released from osmotic pump tablets was similar with that from liquid self-microemulsion in morphology and size through transmission electron microscope and dynamic light scattering. Furthermore, the effect of osmotic pump tablet on the release of microemulsion droplets was similar with that of small molecular drugs in osmotic pump tablets. Briefly, the release rate of the microemulsion was proportional to osmotic pressure of osmotic agent, ratio of osmotic agent to suspending agent, content of pore maker, and size of release orifice, while it was inversely proportional to thickness of semipermeable membrane.In vivo investigation demonstrated the oral bioavailability of both self-microemulsion osmotic pump tablet (SMEOPT) and tablet core had no significance with commercial Sandimmune Neoral(?) and the former evidently prolonged effect after oral administration to Beagle dogs. Thus, the osmotic pump tablets had potential to be a control release system of nanoparticles.更多还原