【作者】 王雪毓；

【导师】 余龙；

【作者基本信息】 华南理工大学 ， 淀粉资源科学与工程， 2011， 博士

【摘要】 近年来,随着现代科学技术的飞速发展及药物制剂理论的不断更新,极大地促进了药物新剂型的发展,使得药物制剂的研究已从简单的传统剂型进入到药物传递系统时代。特别是口服缓控释给药系统更是凭借其较高的用药安全性和生物利用度已经成为当今医药工业发展的一个重要方向。由此而引起的研制和开发适合的新型载体材料及相关制剂技术,建立有效的给药体系已成为当前制药业的迫切任务。因此,开发适合水分散体薄膜包衣的淀粉口服药物缓控释载体材料和包衣技术既符合现代给药系统的发展趋势,也能拓宽淀粉在医药领域的应用,具有重大的理论意义和经济价值。采用高温高压-酶解协同修饰方法对淀粉进行改性,获得重均聚合度范围较宽的改性淀粉,使其符合缓控释给药系统的要求;并利用多功能显微、傅里叶变换红外光谱分析、X-射线衍射、小角X-射线散射和凝胶渗透色谱-激光光散射联用等技术对改性前后的淀粉结构和性质进行研究。以改性淀粉作为微丸薄膜包衣的新材料,根据水分散体薄膜包衣材料的制备要求及其包衣特点,研究了淀粉基水分散体的流变学规律、粒径、稳定性等性质。采用流延法制备淀粉游离膜,并对其成膜性、透湿性以及在模拟人工胃液和模拟人工肠液中的消化性能进行了研究,建立了适合水分散体薄膜包衣的淀粉包衣液体系。以5-氨基水杨酸和胰岛素为模型药物,采用挤出滚圆技术制备载药丸芯,探索了包衣条件对包衣效果及微丸释药性能的影响,建立了低温水分散体包衣技术,在研究各种因素对制剂成型的影响和优化制剂工艺的基础上,构建淀粉基水分散体薄膜包衣缓控释微丸新型给药系统。体外模拟实验结果表明,当以水为溶剂,选取重均分子量为3.07×10~4g/mol的改性淀粉作为薄膜包衣材料,包衣液固含量为8%(w/w),选择1,2-丙二醇作为增塑剂,其添加量为10%(w/w),控制包衣增重量为30%(w/w),所制得的薄膜包衣微丸无论是载小分子的化学药物还是多肽蛋白质大分子药物,在模拟人工胃液和人工小肠液中的释药率约为28.26%,在模拟结肠环境中释放30h后释药率可达90%左右,表明所制备的改性淀粉基水分散体薄膜包衣微丸具有良好的缓控释释药性能,其释药机制主要为扩散控制释放机制以及渗透压驱动作用协同机制,释药速率取决于淀粉膜的结构与性质、包衣厚度、模型药物分子量及其在溶出介质中的溶解性、衣膜中的扩散性等。所建立的释药动力学方程符合零级动力学模型、Ritger peppas方程和Logistic模型。采用Ⅱ型糖尿病大鼠模型和先进的免疫组化技术,对载体材料和给药系统在大鼠消化道中的药物释放行为和药效学等进行验证和评价。研究结果表明,在同等有效的胰岛素剂量水平下,淀粉基水分散体薄膜包衣胰岛素微丸制剂则呈现出较好的药物缓控释性能,无“血糖波动”和“低血糖”现象出现,释放规律良好,与体外模拟实验结果趋势一致。本论文以自然界中资源丰富和生物相容性好的高直链玉米淀粉作为研究对象,通过物理重组协同酶修饰技术,获得了具有良好耐酸和耐酶解性能的改性淀粉,以其作为水分散体薄膜包衣载体材料所构建的膜控型微丸给药系统具有良好的药物缓控释性能,能够保护药物生理活性,延长药物释放时间,提高药物给药效果。这将为淀粉作为水分散体包衣薄膜以满足药物在消化道的缓控释放奠定了基础,也为淀粉深加工及可再生资源的高附加值利用提供了新的思路。更多还原

【Abstract】 In recent years, the rapid development of modern science and technology and the update of pharmaceutical preparations theories greatly promoted the development of new drugs formulations, which pushed the study of pharmaceutical preparations from a simple-traditional form to a drug delivery system. In particular, oral sustained and controlled release delivery system has become an important direction of pharmaceutical industry due to its high drug safety and bioavailability. Development of new carrier materials and related preparation technologies, establishment of effective drug delivery systems have become an urgent tasks for the pharmaceutical industry. Based on these requirements,the development of suitable starch-based aqueous dispersion film coating sustained and controlled release carrier materials and coating technology are in line with the trend of modern drug delivery systems, and can also expand the application in the pharmaceutical field of starch, have both great scientifical importance and commercial value.Various weight-average degree of polymerization of modified starch were obtained by using high temperature and high pressure-enzyme collaborative method to meet the requirements of sustained and controlled release drug delivery systems.The structure and properties of modified starch were studied by multi-functional microscope, fourier transform infrared spectroscopy, X-ray diffraction, small angle X-ray scattering and gel permeation chromatography-laser light scattering techniques.As new film coating materials from the modified stach, the rheology, particle size, stability and other properties of the starch-based aqueous dispersion were studied according to preparation requirements and coating characteristics of aqueous dispersion film coating material. Free starch films were prepared by using cast method, the film-forming properties, moisture and digestive properties in simulated human gastric and small intestinal fluid were also studied. A suitable starch-based aqueous dispersion film coating system was developed.Using 5-amino salicylic acid and insulin as model drugs, the drugs pellets were prepared by extrusion-spheronisation. The effect of coating conditions on the coating and the release properties were investigated, the low temperature aqueous dispersion coating technology was established. The starch-based aqueous dispersion film coating sustained and controlled drug delivery system was constructed on the base of investigation of the influence of different factors on the formation of the drug delivery system and optimization of the preparation processes. The results from in-vitro tests indicated that the constructed drug delivery system was suitable for delivering not only the small molecular chemical drug but also biomacromolecule drugs, when using water as solvent, the weight average molecular weight 3.07×104g/moL of modified starch as film coating materials, solid content of 8% (w / w) ,1,2 -propylene glycol as a plasticizer and its addition level of 10%(w/w), coating weight of 30%(w/w), the drug release of approximately 28.26% in simulated gastric fluid and small intestinal fluid, after 30h the release about 90% in the simulated colon fluid, providing with good sustained and controlled performance. The release mechanism are mainly diffusion controlled release mechanism and osmotic pressure-driven coordinative mechanism, The drug release rate depends on the structure and properties of starch films, coating thickness, the molecular weight of a model drug and its solubility in the dissolution medium, the diffusion in the coating films. The established dynamic equation corresponds to zero order release kinetic model, ritger peppas equation and logistic models.The typeⅡdiabetic rat m odel and advanced im m unohisto-chemistry technology were used to validate and evaluat the releasing properties and pharmacodynamics of carrier materials as well coated pellets in the rat gastrointestinal tracts. The results suggest that starch-based aqueous dispersion film coating insulin pellets have a good drug release performance at the same effective dose of insulin, have no blood glucose fluctuations phenomenon and low blood glucose phenomenon, and have the same trend with in-vitro results.In this thesis, use high amylose corn starch which rich in nature and has good biocompatibility as a research object, good resistance to acid and enzyme properties of modified starch was obtained by physical restructuring-enzyme collaborative method. The modified starch as aqueous dispersion film coating carrier constructed film-controlled pellet delivery system and protected the physiological activity of drugs, prolonged drug release time and improve the administration effect of drug. This work not only provides foundation for aqueous dispersion coating film to meet sustained and cotrolled drug release in the digestive tract, but also provides a new way of the deep-applications of starch. Furthermore, materials from the renewable resources will be utilized as a higher value product.更多还原