胰岛素长效载药系统的制备与药效学评价

发布时间：2018-04-23 21:52

本文选题：SAIB载药贮库 + 体外释放　；参考：《河北大学》2017年硕士论文

【摘要】：乙酸异丁酸蔗糖酯(sucrose acetate isobutyrate,SAIB)能溶解于具有生物相容性的有机溶剂中,只需很少的溶剂量就可将SAIB溶液的黏度降低至适于注射的范围。在注射给药后,溶剂与水进行互换,蔗糖酯在注射部位生成沉淀,药物则被固态基质包裹,经溶出、扩散等缓慢释放。聚乳酸(polylactic acid,PLA)是以淀粉为原料发酵生成乳酸,再经化学聚合而成的聚合物。PLA可在人体内降解生成乳酸,最终代谢为水和二氧化碳。聚乳酸具有良好的生物相容性,美国FDA已批准聚乳酸用作医用和缓控释药物的材料。胰岛素(INS)临床上用于Ⅰ型糖尿病、部分Ⅱ型糖尿病、妊娠糖尿病及各种继发性糖尿病的治疗,由于胰岛素直接口服无治疗效果,目前主要依靠皮下注射途径给药。为了降低糖尿病人因频繁注射胰岛素所带来的痛苦,减少给药频率,本论文选用PLA和SAIB为载药基质,构建了两种新型的胰岛素载药系统:胰岛素-SAIB载药贮库以及胰岛素PLA植入片,以期延长胰岛素的作用时间,减少血糖波动,提高患者顺应性。本文建立了胰岛素-SAIB载药贮库以及胰岛素PLA植入片的体外高效液相色谱分析方法,方法学考察结果均符合相关规定。考察了SAIB/无水乙醇溶液系统的流变学性质,20%(w/w)无水乙醇的SAIB溶液系统的黏度为0.14 Pa?s,表明20%的乙醇就能把SAIB溶液的黏度降至可注射范围内。选用高压均质法及冻干法制备了不同均质次数的胰岛素冻干粉末,采用复乳溶剂挥发法制备了INS-PLA载药微球。使用扫描电子显微镜、傅里叶变换红外光谱仪、差示扫描量热仪、X射线粉末衍射仪对制备的微球进行表征,并测定微球的包封率及载药量。结果表明微球表面光滑、球形度良好,胰岛素均匀地分布在聚乳酸微球中。分别以不同均质次数的胰岛素冻干粉末、胰岛素PLA微球为主要药物,SAIB为基质,无水乙醇为溶剂,制备胰岛素-SAIB载药贮库。进行了胰岛素PLA微球-SAIB载药贮库的体外释放实验,释放12小时,胰岛素的累积释放量达到34.5±2.5%,随后释放速率放缓,96小时后,胰岛素的累积释放量达到72.1±2.9%。制备了胰岛素PLA植入片,通过体外的分散性实验及皮下埋植实验筛选出了两种亲水性辅料:泊洛沙姆188,泊洛沙姆407。体外释放性实验表明,植入片中泊洛沙姆与PLA的比例及不同型号的泊洛沙姆共同造成了各植入片在释放速度上的差别。12小时后,各处方下植入片的累积释药量达到70.6±1.8%?84.8±1.6%。扫描电镜显示了皮下植入后植入片产生的孔洞结构,这是由于泊洛沙姆188和泊洛沙姆407的水溶性良好,能够持续溶解,可在植入片内外形成浓度梯度,在向体液释放过程中,形成了微小孔道。植入片表面和浅表层的胰岛素通过扩散作用直接进入释放介质中,植入片内部的胰岛素通过PLA基质中泊洛沙姆溶蚀出的孔道向外扩散。以Wistar雄性大鼠为实验动物,选用链脲佐菌素为动物糖尿病诱发剂,制备了Ⅱ型糖尿病大鼠模型,分别对胰岛素-SAIB载药贮库以及胰岛素PLA植入片的体内药效学进行了研究。实验数据表明胰岛素-SAIB载药贮库及胰岛素PLA植入片均有较好的降血糖作用。同样剂量(10 IU/kg)下,前4 h载有胰岛素PLA微球的SAIB贮库系统与胰岛素PLA植入片都有突释现象发生,但随后都稳定在一个平台期。载有胰岛素PLA微球的SAIB贮库系统的有效作用时间约为120 h。胰岛素PLA植入片的有效作用时间约为84 h。肌肉刺激性实验结果表明胰岛素-SAIB贮库的肌肉刺激性小,生物相容性良好。
[Abstract]:Sucrose acetate isobutyrate (SAIB) can be dissolved in biocompatible organic solvents. The viscosity of SAIB solution can be reduced to the scope suitable for injection by only a small amount of solvent. After injection, the solvent is exchanged with water, the sucrose ester is deposited at the injection site, and the drug is solid matrix. The polylactic acid (PLA) is fermented with starch to produce lactic acid, and then the polymer.PLA is chemically polymerized to produce lactic acid in the human body and eventually metabolized to water and carbon dioxide. Polylactic acid has good biocompatibility. The United States FDA has approved polylactic acid as medical and medical treatment. Materials. Insulin (INS) is used clinically for type I diabetes, partial type II diabetes, gestational diabetes and the treatment of various secondary diabetes. It is mainly dependent on subcutaneous injection to reduce the pain caused by frequent insulin injection because of the direct oral administration of insulin without treatment. In order to reduce the frequency of drug delivery, this paper uses PLA and SAIB as the carrier matrix, and constructs two new types of insulin carrier system: insulin -SAIB carrier storage and insulin PLA implant. In order to prolong the action time of insulin, reduce the fluctuation of blood sugar and improve the patient's compliance. This paper established insulin -SAIB carrying storage and insulin PLA. The results of the high performance liquid chromatography analysis in vitro were all in accordance with the relevant regulations. The rheological properties of the SAIB/ anhydrous ethanol solution system were investigated. The viscosity of the SAIB solution system of 20% (w/w) anhydrous ethanol was 0.14 Pa? S, indicating that the viscosity of the 20% ethanol could reduce the viscosity of the SAIB solution to the injectable range. The insulin freeze-dried powder with different homogenization times was prepared by the method of lyophilization and the INS-PLA loaded microspheres were prepared by the volatile solvent evaporation method. The microspheres were characterized by scanning electron microscope, Fourier transform infrared spectrometer, differential scanning calorimeter and X ray powder diffractometer, and the encapsulation efficiency and drug loading of the microspheres were measured. The results showed that the surface of the microspheres was smooth and the degree of sphericity was good. The insulin was evenly distributed in the polylactic acid microspheres. The insulin PLA microspheres were used as the main drug, the SAIB as the main drug, the SAIB as the substrate and the anhydrous ethanol as the solvent to prepare the insulin -SAIB carrier storage tank. The body of insulin PLA microspheres -SAIB drug storage storage body was carried out. The release of external release was 12 hours, the cumulative release of insulin was 34.5 + 2.5%, and the subsequent release rate slowed. After 96 hours, the cumulative release of insulin reached 72.1 + 2.9%., and the insulin PLA implant was prepared. Two hydrophilic excipients were selected through the dispersive experiment in vitro and the subcutaneous implant screening test. Pooper Losham 188, poloxa The in vitro release test of M 407. showed that the proportion of poloxamer and PLA in the implant and the different models of poloxamer caused the difference in the rate of release for.12 hours. The cumulative release of the implanted tablets under each prescription reached 70.6 + 1.8%? 84.8 + 1.6%. scanning electron microscopy. The structure, which is due to the good water solubility of poloxamer 188 and poloxamer 407, can dissolve continuously, and can form a concentration gradient within and outside the implant tablet. In the process of releasing the body fluid, a micro channel is formed. The insulin on the surface of the implant and the superficial layer of insulin enters the release medium through diffusion, and the internal insulin in the implant is passed through P The passage of poloxamer dissolved in the LA matrix was spread out. Taking Wistar male rats as experimental animals and using streptozotocin as an animal diabetes inducer, the model of type II diabetic rats was prepared. The pharmacodynamics of insulin -SAIB carrying storage and insulin PLA implanted tablets were studied. The experimental data showed that the islets of the islets were islet. In the same dose (10 IU/kg), both the SAIB storage system of the first 4 h containing insulin PLA microspheres and the insulin PLA implanted tablets all have a sudden release phenomenon, but they all stabilized at a plateau period. The effective effect of the SAIB storage system containing islet PLA microspheres is effective at the same dose (10 IU/kg). The effective time of the 120 h. insulin PLA implant was about 84 H., and the muscle irritation of the insulin -SAIB storeroom was small and the biocompatibility was good.

【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;R965

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