新型肠溶包衣材料水分散体的制备及性能研究

发布时间：2018-05-06 09:24

本文选题：水分散体制备 + Eudragit(?)L30D-55　；参考：《浙江大学》2014年硕士论文

【摘要】：肠溶包衣已经被广泛用于提高对酸敏感药物的化学稳定性,减少胃刺激及靶向药物在结肠释放等领域。有机溶剂包衣是较为传统的包衣技术,通过溶剂蒸发形成结构较为致密,水分不容易透过的聚合物膜。但有机溶剂包衣特别是用于微丸包衣时其较高的粘度会给包衣带来不便,且由于有机溶剂毒性大、易挥发、易燃易爆、价格昂贵、存在潜在环境污染等缺点,其应用推广受到了一定限制。聚合物水分散体包衣是一种以水为分散介质的复杂体系,具有毒性低、粘性低、包衣效率高等优点。现有常用水分散体包衣液中的包衣材料分子及增塑剂分子,主要呈现各自聚集形成固态或半固态的球形粒子特征,增塑剂与包衣材料分子之间相互扩散产生分子交互作用程度不足,导致水分散体包衣膜的结构致密性不及有机溶剂膜。本研究制备了一种新型的肠溶材料水分散体。先将肠溶包衣材料Eudragit(?)L100-55溶于有机溶剂,加入增塑剂柠檬酸三乙酯(Triethyl citrate, TEC),必要时加入其他附加剂溶解,加入处方量水乳化均匀后,挥发除去有机溶剂制备得到水分散体包衣液(Eudragit(?)L100-55水分散体包衣液)。采用铸膜法分别制备Eudragit(?)L100-55水分散体、Eudragit(?)L100-55有机溶剂、Eudragit(?)L30D-55水分散体游离膜。考察上述游离膜的外观,以差示扫描量热法(Differential scanning calorimetry, DSC)测定薄膜玻璃化转变温度(Glass transition temperature, Tg),杯法考察薄膜的透湿性能,转篮法测定游离膜在不同介质中的溶解性能。结果显示,当TEC浓度同为5%时,Eudragit(?)L100-55水分散体膜的渗透性能接近于Eudragit(?)L100-55有机溶剂膜,二者的膜渗透性均明显小于市售Eudragit(?)L30D-55水分散体膜。当TEC浓度分别为10%及20%时,Eudragit(?)L30D-55水分散体膜的Tg分别为58.17℃及50.95℃,Eudragit(?)L100-55水分散体膜的Tg分别为53.63℃及41.72℃,Eudragit(?)L100-55有机膜的Tg分别为51.70℃及32.25℃,显示Tg的大小排序为：Eudragit(?)L30D-55水分散体膜Eudragit(?)L100-55水分散体膜Eudragit(?)L100-55有机膜。在相同浓度增塑剂条件下,Eudragit(?)L100-55水分散体膜的Tg、透湿性均低于Eudragit(?)L30D-55水分散体膜。同等条件下,Eudragit(?)L100-55水分散体膜在O.lmol/L盐酸中溶解性明显小于Eudragit(?)L30D-55水分散体膜,显示其耐酸力强于Eudragit(?)L30D-55水分散体膜。以泮托拉唑钠(Pantoprazole sodium, PAZ-Na)为模型药物,挤出滚圆法制备含药丸芯,流化床底喷包衣。以羟丙基甲基纤维素(Hydroxypropyl methyl celulose, HPMC)为隔离层膜材,分别以Eudragit(?)L30D-55水分散体、Eudragit(?)L100-55水分散体、Eudragit(?)L100-55有机溶液为肠溶材料,制备PAZ-Na肠溶微丸,研究肠溶包衣后微丸的耐酸力及释药情况。在包衣过程中,发现Eudragit(?)L100-55水分散体粘度低于Eudragit(?)L1100-55有机溶液,且包衣时间明显缩短。当肠溶衣增重9%时,比较Eudragit(?)L30D-55水分散体肠溶衣微丸、Eudragit(?)L100-55有机溶液肠溶衣微丸和Eudragit(?)L100-55水分散体肠溶衣微丸的耐酸性,在0.1mol/L盐酸耐酸力实验中,发现三种肠溶微丸中药物剩余量分别为76.21%、86.44%及85.19%。相应的,三种肠溶微丸在酸中的药物损失量,分别为23.79%、13.56%及14.81%；当肠溶衣增重12%时,三种肠溶微丸中药物剩余量分别为88.87%、94.52%及93.78%,相应的,三种肠溶微丸在酸中的药物损失量,分别为11.13%、5.48%及6.22%。显示Eudragit(?)L100-55有机膜和Eudragit(?)L100-55水分散体膜的耐酸性,明显高于Eudragit(?)L30D-55水分散体膜。研究结果发现,自制的Eudragit(?)L100-55水分散体,在较小的包衣增重(9%)条件下制备得到的肠溶微丸的耐酸性,接近于市售Eudragit(?)L30D-55水分散体在较大包衣增重(12%)条件下得到的肠溶微丸的耐酸性,显示其在减少包衣材料用量及增强包衣效率上的优势。本课题的研究结果显示,通过乳化蒸发法制备得到的Eudragit(?)L100-55水分散体,其肠溶膜的热力学性质、透湿性、溶解性及耐酸性等理化性质,均体现出接近于Eudragit(?)L100-55有机膜,且优于Eudragit()L30D-55水分散体膜,同时保持了水分散体包衣快速、便捷的优点,是一种有良好应用前景的新型包衣水分散体。
[Abstract]:Enteric coated coating has been widely used to improve the chemical stability of acid sensitive drugs, reduce the gastric irritation and the release of the target drug in the colon. Organic solvent coating is a more traditional coating technology, and evaporates to form a dense polymer membrane through solvent evaporation, but the organic solvent coating is especially used for micro coating. The high viscosity of the pellets will bring inconvenience to the coating, and because the organic solvent is toxic, volatile, flammable, explosive, expensive, and has the potential environmental pollution, its application is limited. The polymer water bulk coating is a complex system with water as the dispersing medium with low toxicity, low viscosity and coating. The coating material molecules and plasticizer molecules in the existing liquid bulk coating liquid are mainly characterized by the formation of spherical particles in solid or semi solid state, and the interaction between the plasticizer and the coating material is insufficient, which leads to the structural densification of the coating membrane. A new type of aqueous dispersion of enteric material was prepared. First, the enteric coated material Eudragit (?) L100-55 was dissolved in the organic solvent, adding three ethyl citric acid (Triethyl citrate, TEC) with the plasticizer, and adding other additives when necessary. After the emulsification of the prescription water was uniform, the organic solvent was prepared by volatilization. Eudragit (?) L100-55 aqueous dispersion, Eudragit (?) L100-55 organic solvent and Eudragit (?) L30D-55 water bulk free membrane were prepared by casting film method (Eudragit (?) L100-55 aqueous dispersion coating solution). The external view of the free membrane was investigated by differential scanning calorimetry (Differential scanning calorimetry, DSC). The membrane glass transition temperature (Glass transition temperature, Tg) was used to investigate the moisture permeability of the film. The solubility of the free film in different media was measured by the method of rotating basket. The results showed that when the concentration of TEC was 5%, the permeability of Eudragit (?) L100-55 aqueous dispersion membrane could be close to Eudragit (?) L100-55 organic solvent membrane and the membrane permeation of the two. When the TEC concentration was 10% and 20%, the Tg of Eudragit (?) L30D-55 water bulk membrane was 58.17 and 50.95, respectively, Eudragit (?) L100-55 water bulk membrane was 53.63 and 41.72, respectively, and Eudragit (?) L100-55 organic membrane was 51.70 and 32.25, respectively, when the TEC concentration was 10% and 20% respectively. The size of the Eudragit (?) L30D-55 aqueous dispersion film Eudragit (?) L100-55 aqueous dispersion membrane Eudragit (?) L100-55 organic membrane. Under the same concentration plasticizer, the Tg of the Eudragit (?) L100-55 water bulk membrane is lower than the Eudragit (?) L30D-55 aqueous dispersion film. Under the same condition, Eudragit (?) The solubility of hydrochloric acid is less than Eudragit (?) L30D-55 aqueous dispersion membrane, which shows its acid resistance is stronger than that of Eudragit (?) L30D-55 aqueous dispersion membrane. Pantoprazole sodium (Pantoprazole sodium, PAZ-Na) is used as a model drug. The extrusion pellet method is used to prepare pill core and fluidization bed spray coating. With hydroxypropyl methyl cellulose (Hydroxypropyl methyl Celulose,) HPMC) for isolation layer film, Eudragit (?) L30D-55 aqueous dispersion, Eudragit (?) L100-55 water bulk, Eudragit (?) L100-55 organic solution as enteric soluble material, PAZ-Na enteric pellets were prepared to study the acid resistance and release of micropellets after enteric coated coating. In the process of coating, the viscosity of Eudragit (?) L100-55 water bulk was lower than Eudragit (? ) L1100-55 organic solution, and the coating time was obviously shortened. When the enteric coat weighed 9%, the acid resistance of Eudragit (?) L30D-55 water dispersible enteric coated pellets, Eudragit (?) L100-55 organic solution pellets and Eudragit (?) L100-55 water dispersible enteric coated pellets were compared. In the acid endurance test of 0.1mol/L hydrochloric acid, three kinds of enteric pellets were found. The residual amount of the material was 76.21%, 86.44% and 85.19%. respectively. The drug loss of three kinds of enteric pellets in acid were 23.79%, 13.56% and 14.81%, respectively. When the enteric coat weighed 12%, the residual amount of drugs in three enteric pellets was 88.87%, 94.52% and 93.78% respectively, and the amount of drug loss of three kinds of enteric pellets in acid was 11.13%, respectively. 5.48% and 6.22%. showed that the acid resistance of Eudragit (?) L100-55 organic film and Eudragit (?) L100-55 water bulk membrane was significantly higher than that of Eudragit (?) L30D-55 aqueous dispersion membrane. The results showed that the self-made Eudragit (?) L100-55 aqueous dispersion and the acid resistance of the enteric pellets prepared under the conditions of smaller coating weight gain (9%) were close to the market Eudrag. The acid resistance of it (?) L30D-55 aqueous dispersions under the condition of large coating weight gain (12%) is shown to reduce the amount of coating materials and enhance the coating efficiency. The results of this study show that the Eudragit (?) L100-55 aqueous dispersion obtained by emulsification evaporation method, the thermodynamic properties of its enteric membrane, and the moisture permeability of its enteric membrane The physical and chemical properties, such as sex, solubility and acid resistance, are close to the Eudragit (?) L100-55 organic membrane, and are superior to Eudragit () L30D-55 water dispersions. It also maintains the quick and convenient advantages of water bulk coating, and is a new type of coating moisture bulk with good application prospect.

【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

【参考文献】