【作者】 黄琳；

【导师】 杨光；

【作者基本信息】 华中科技大学 ， 生物制药工程， 2013， 博士

【摘要】 细菌纤维素(BC)是一种天然、易得、无毒并具有纳米级的网络结构的纤维素,具有开发为新型药物载体的潜力。脂质体作为一种研究得比较成熟的药物载体,具有类细胞结构、靶向性、减少药物毒副作用等优点。本文分别选取BC膜和脂质体以及两者的复合物作为药物缓释载体,以对心脏病、糖尿病和癌症等方面有良好疗效但生物利用度低的盐酸小檗碱(BH)和硫酸小檗碱(BS)作为模式药物,来制备出具有缓释、提高药物生物利用度的药物缓释系统。新型药物载体BC天然的超精细的纳米网络结构是其具有缓释能力的基础。通过对药物缓释系统制备方式的筛选,确定了冻干10mm厚的BC膜的缓释效果是最好的。比起市售药片,BC可以显著延长药物释放时间。扫描电子显微镜(SEM)分析证明了酸和碱通过对BC纤维发生溶胀作用而影响缓释行为。药物缓释行为最符合Ritger Peppas模型中的自由扩散机制。对药物和载体的相互作用机制也进行了深入探讨,’H高分辨率魔角旋转核磁共振扩散排序谱(1H NMR HRMAS DOSY)分析证明药物和BC之间存在着疏水作用。BC的生物相容性、尺寸的生物可控性、高机械强度和稳定的物理化学性质使BC具有开发为口服药物载体的潜力。用薄膜蒸发法和主动载药法制备了小檗碱脂质体,空白脂质体的平均粒径约为80nm,载药脂质体的粒径增加到110-160nm。PDI均小于0.2,单分散性良好。脂质体表面基本呈电中性。药物的包封率达到药典规定的80%以上。透射电子显微镜(TEM)观察到脂质体呈球形,具有核-壳结构。药物的释放受到缓释环境pH变化的影响。大部分的缓释行为符合Ritger Peppas模型中的药物自由扩散和骨架溶蚀相协同的机制。动物实验证明,小檗碱脂质体的峰浓度(Cmax)、药-时曲线下面积(AUC)等比小檗碱溶液明显增加了,其中以BS脂质体最好。因此,此载药脂质体的制备方法良好,达到了缓释和提高药物生物利用度的双重目的。为了增强脂质体的稳定性,采用机械强度高的BC包裹脂质体。考察了3种方法复合BC和脂质体,以原位合成的方法最好。此复合物集合了BC和脂质体的优点,具有稳定性高和与细胞亲和的双重优点,并且,可以达到在胃环境中减少药物释放,在小肠环境中增加药物释放的目的。BC作为一种新型的口服药物载体材料,缓释性能良好,且具有pH响应性。脂质体不仅具有缓释效果,还提高了小檗碱的生物利用度。两者的复合物结合了各自的优势,开启了寻求既坚固稳定又具有缓释能力和提高药物入血吸收的新型载体的探索。更多还原

【Abstract】 Bacterial cellulose (BC) is natural, easy to get, non-toxic and has a nanoscale network structure, which has the great potential applications for novel drug carriers. Liposome, as a mature drug carrier, has cell-like structure, targeting property, reducing drug side effects and other advantages. In this paper, we chose BC membrane, liposome and the BC-liposome complex as drug delivery, berberine hydrochloride and berberine sulfate with good effect on heart disease, diabetes and cancer but low bioavailability as the model drug to prepare the drug delivery systems with the properties of controlled release and good bioavailability.The naturally hyperfine nano-network structure of BC gives its sustained-release property as the novel drug carrier. The Prepared methods were screened, and freeze-dried BC membranes with the thickness of10mm were found the optimal for drug delivery. Compared to commercially available tablets, BC can significantly prolong the drug release time. Scanning electron microscopy (SEM) analysis demonstrated that the acid and alkali influenced the release behavior by swelling the BC fibers. The release curves closely followed the Ritger-Peppas model with free diffusion as the most prominent mechanism. The interaction mechanism between drug and carrier was discussed deeply.’H high-resolution magic angle spinning nuclear magnetic resonance (1H HRMAS NMR) diffusion-ordered spectroscopy (DOSY) analysis showed that hydrophobic interactions existed between BC and drug. The biocompatibility, size bio-controllability, high mechanical strength and physicochemical stability of BC makes it can be developed as a promising oral drug carrier.The drug-loaded liposomes were prepared by the thin-film evaporation and active drug-loaded method. The average size of blank liposome particle was about80nm, and after loading drug, the particle sizes were increased to110-160nm. All PDI were below0.2, which means the narrow size distributions. Liposomes were substantially electrically neutral. The encapsulation efficiency of drug was high, more than80%. The morphologies of liposomes were observed by transmission electron microscopy (TEM). They were spherical with the core-shell structure.The sustained release of drug-loaded liposomes exhibited a pH response property. The release curves closely followed the Ritger-Peppas model with both the drug free diffusion and skeleton dissolution as the most prominent mechanisms. Animal experiments demonstrated that the peak concentration of berberine (Cmax) and area under concentration-time curve (A UC) of liposome-berberine were significantly increased compared to berberine solution. Therefore, the preparation methods of liposomes were good, which can achieve the dual purpose of improving release behaviors and bioavailability of drug.In order to enhance the stability of liposomes, BC with high mechanical strength was added. Three different methods were used to synthesize BC and liposome composite, and in situ synthesis method was the best. This complex combines the advantages of BC and liposomes, with the dual advantages of cell affinity and high stability. Moreover, this complex can achieve the purposes of reducing drug release in stomach and increasing drug release in small intestine.BC as a novel oral drug carrier material, shows good performance of sustained-release, and has pH-responsive property. Liposome-based drug carrier, not only has sustained effects, but also can significantly increase the berberine absorption into the blood. The complex combined their respective strengths and started exploring the new carrier which is strong and stable, possesses sustained release capacity and can improve bioavailability of drug.更多还原