胰岛素长效释药系统在糖尿病治疗中的研究

发布时间：2018-05-26 02:42

本文选题：植入剂 + 胰岛素　；参考：《河北大学》2017年硕士论文

【摘要】：胰岛素,是一种蛋白质激素,由胰脏内的胰岛β细胞分泌。胰岛素参与调节糖代谢,控制血糖平衡,可用于治疗糖尿病。目前注射给药依然是胰岛素临床应用的主要给药方式。由于胰岛素的半衰期短、生物利用度差,胰岛素制剂一天之内需要注射3-4次,这给患者带来了巨大的痛苦。因此,开发新的胰岛素长效递送系统是非常重要的。本课题系统地研究了两种植入剂型对胰岛素的缓释作用。(1)制备泊洛沙姆水凝胶,以胶凝温度和黏度为指标,通过考察P407与P188不同比例及辅料对成胶温度及黏度的影响,确定出较佳的处方进行表征,然后分别在凝胶中载入胰岛素纳米粒和微球进行体内外的研究。(2)制备了胰岛素固体植入剂,通过调节PLGA与亲水性物质(透明质酸钠、羧甲基纤维素钠)的比例,筛选出合适的处方,进行降血糖的药效学研究。本文第一部分用高效液相色谱法建立了胰岛素含量测定的方法学。测定结果显示胰岛素在0.5-10IU/mL范围内浓度与峰面积呈良好的线性关系。该方法的稳定性、精密度、回收率结果均符合规定,辅料不干扰胰岛素的测定,说明本色谱条件专属性良好适用于胰岛素的测定。同时本章还建立了大鼠糖尿病模型的方法,确定了采用葡萄糖氧化酶的方法测定血糖。本文第二部分对泊洛沙姆注射植入剂进行了处方筛选及处方优化,以胶凝温度和时间为评价指标筛选出合适的凝胶处方,最终选择P188:P407:HPMC=9:20:3、P188:P407:SA=9:20:2和P188:P407=9:20三个处方,并从黏度、傅里叶红外光谱、扫描电镜等方面进行表征。将胰岛素晶体或胰岛素微球加载到优化后的处方中进行体内外释放的研究。实验结果表明,温敏水凝胶加载胰岛素微球的处方的降糖效果可以持续72 h。本文第三部分对胰岛素固体植入剂进行了处方筛选,固体植入剂的载体为可降解的PLGA及亲水性物质(泊洛沙姆188、泊洛沙姆407、透明质酸钠、羧甲基纤维素钠),以体外溶蚀为指标选出合适的处方进行研究。从实验结果可以看出,胰岛素固体植入剂可持续平稳降血糖96 h。这显著减少了胰岛素的给药次数,提高了患者的适应性。
[Abstract]:Insulin, a protein hormone, is secreted by islet-尾 cells in the pancreas. Insulin is involved in regulating glucose metabolism, controlling blood glucose balance, and can be used in the treatment of diabetes. At present, intravenous administration is still the main way of insulin clinical application. Because of the short half-life and low bioavailability of insulin, insulin preparations need to be injected 3-4 times a day, which brings great pain to patients. Therefore, the development of new insulin delivery system is very important. The preparation of Poloxamer hydrogel was studied systematically. The effects of different ratios of P407 and P188 and excipients on the gelation temperature and viscosity were investigated. Insulin solid implants were prepared by adjusting PLGA and hydrophilic substances (sodium hyaluronate, sodium hyaluronate). The proportion of carboxymethyl cellulose sodium, screening out the appropriate prescription, hypoglycemic pharmacodynamics study. In the first part of this paper, a method for the determination of insulin was established by high performance liquid chromatography (HPLC). The results showed that the concentration of insulin in the range of 0.5-10IU/mL showed a good linear relationship with the peak area. The stability, precision and recovery of this method are in accordance with the requirements, and the excipients do not interfere with the determination of insulin, indicating that the chromatographic conditions are suitable for the determination of insulin. At the same time, the method of glucose oxidase was established to determine blood glucose in diabetic rats. In the second part of this paper, the formulation of Poloxamer injection implant was selected and optimized. The gelation temperature and time were taken as the evaluation index to select the appropriate gel prescription. Finally, P188: P407: HPMC 9: 20: 3 and P188: P407: SA9: 20: 2 and P188:P407=9:20 were selected, and three prescriptions were obtained according to the viscosity of P188: P407: HPMC 9: 20: 3 and P188: P407: SA9: 20: 2 and P188:P407=9:20. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and other aspects were characterized. Insulin crystals or insulin microspheres were loaded into optimized prescriptions for in vitro and in vivo release studies. The results showed that the hypoglycemic effect of insulin microspheres loaded with thermo-sensitive hydrogel could last for 72 h. In the third part of this paper, the insulin solid implants were selected. The carriers of the solid implants were biodegradable PLGA and hydrophilic substances (Poloxamer 188, Poloxamer 407, sodium hyaluronate, sodium hyaluronate). Sodium carboxymethyl cellulose (CMC) was used as the index of dissolution in vitro. It can be seen from the experimental results that insulin solid implants can steadily and steadily reduce blood glucose for 96 h. This significantly reduces the frequency of insulin administration and improves patient adaptability.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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