胰岛素长效植入制剂的制备及评价

发布时间：2018-07-15 12:25

【摘要】：胰岛素是一种蛋白质激素,由胰脏内的胰岛细胞分泌,可以调节糖代谢和控制血糖水平,主要用于治疗糖尿病,由于胰岛素为多肽链,直接口服会被胃肠道消化酶降解失活,注射是其主要给药途径,长效缓释、控释药物制剂是研究较多的领域,植入剂可避免胰岛素口服降解的问题。植入剂的材料为高分子化合物,本课题选用壳聚糖和PLGA作为皮下植入剂的辅料,以制备稳定性及生物利用度较高、生物毒性低的胰岛素植入剂,对植入剂的处方及制备工艺进行研究,并对该植入剂对糖尿病大鼠的药效学进行研究,具体内容如下:建立了胰岛素外高效液相测定方法,并对方法学进行验证。药物浓度在0.5-10 IU/mL范围内,线性曲线关系A=800396C-12612,R2=0.9999,说明该方法专属性、线性关系良好。精密度及稳定性RSD值均小于1.7%,本法具有较高的灵敏度和准确度。建立了胰岛素的药效学测定方法,使用STZ制备糖尿病大鼠,葡萄糖氧化酶法测定血糖,为后续确定处方及药效测定方法提供依据。温敏凝胶植入剂的制备及评价,以凝胶温度和注射的难易程度为评价指标,确定温敏凝胶的配制,并考察加入辅料后对其凝胶时间的影响,对凝胶的热可逆性、稳定性和结构进行考察,筛选出最佳凝胶比例,使用高压匀质机制备不同粒径的胰岛素微粒,将微粒载入温敏凝胶中,皮下注射给药后测定大鼠血糖,肌肉组织刺激实验,最后确定优化处方为:CS/β-GP+HP-β-CD温敏凝胶加载胰岛素微粒。使用喷雾干燥法制备胰岛素微球,制备的微球形态大小、晶型状态、重新分散性载药量进行研究,微球外观形态不规则,大小不一,载药量为18.5%(EC1:3)和43%(EC1:1)将胰岛素微球载入CS/β-GP+HP-β-CD中进行药效学考察,加载胰岛素微球的CS/β-GP+HP-β-CD在糖尿病大鼠皮下注射后的低血糖作用持续72 h,比胰岛素注射液和甘精胰岛素制剂引起的低血糖效应长得多。使用PLGA为载体制备植入片剂,将胰岛素加载到PLGA中,加入CMC-Na/HA作为致孔剂,用压片法制备可植入片剂,通过体内和体外实验对片剂进行筛选,将片剂植入体内后,片剂降解明显,并且PLGA:CMC-Na比例为2.5:1时,糖尿病大鼠皮下植入后的低血糖作用持续108 h。
[Abstract]:Insulin is a protein hormone secreted by islet cells in the pancreas, which regulates glucose metabolism and controls blood sugar levels. It is mainly used in the treatment of diabetes. Injection is the main way of drug delivery, long-term sustained release, controlled release drug preparation is a lot of research areas, implants can avoid the problem of oral insulin degradation. In this paper, chitosan and PLGA were used as excipients of subcutaneous implants to prepare insulin implants with high stability, bioavailability and low biotoxicity. The prescription and preparation process of the implants were studied. The pharmacodynamics of the implants in diabetic rats was studied. The main contents were as follows: a method for the determination of extracorporeal insulin was established and the methodology was validated. In the range of 0.5-10 U / mL, the linear curve was A _ (800396C-12612N) R _ (2) 0.9999, indicating the specificity of the method and the good linear relationship. The RSD values of precision and stability are less than 1.7. The method has high sensitivity and accuracy. A pharmacodynamic method for the determination of insulin was established. The diabetic rats were prepared by STZ and glucose oxidase method was used to determine the blood glucose. The preparation and evaluation of thermosensitive gel implants were determined according to the gel temperature and the degree of difficulty in injection. The influence of the addition of excipients on the gelation time and the thermal reversibility of the gel were investigated. The stability and structure of the gel were investigated, the optimum gel ratio was screened out, and different particle sizes of insulin were prepared by high pressure homogenizer. The particles were loaded into the thermo-sensitive gel. The blood glucose and muscle tissue stimulation were measured after subcutaneous injection. Finally, the optimized formulation was determined as: 1. CS / 尾-GP HP- 尾-CD thermo-sensitive gel loaded with insulin particles. Insulin microspheres were prepared by spray drying method. The morphology, crystalline state and redispersible drug loading of the prepared microspheres were studied. The appearance of the microspheres was irregular and varied in size. The insulin microspheres were loaded with 18. 5% (EC1: 3) and 43% (EC1: 1) into CSS / 尾 -GP HP- 尾 -CD to investigate their pharmacodynamics. The hypoglycemic effect of CS- / 尾 -GP HP- 尾 -CD loaded with insulin microspheres in diabetic rats was 72 h after subcutaneous injection, which was much longer than that induced by insulin injection and insulin glargine preparation. The implanted tablets were prepared with PLGA as carrier, insulin was loaded into PLGA, CMC-Na / HA was added as pore-forming agent, and implantable tablets were prepared by pressing tablets. The tablets were screened by in vivo and in vitro experiments, and the tablets degraded obviously after the tablets were implanted into PLGA. When the ratio of PLGA: CMC-Na was 2.5: 1, hypoglycemia of diabetic rats after subcutaneous implantation lasted 108 h.
【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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