胰島素長效植入制劑的制備及評價
發(fā)布時間：2018-07-15 12:25
【摘要】：胰島素是一種蛋白質(zhì)激素,由胰臟內(nèi)的胰島細胞分泌,可以調(diào)節(jié)糖代謝和控制血糖水平,主要用于治療糖尿病,由于胰島素為多肽鏈,直接口服會被胃腸道消化酶降解失活,注射是其主要給藥途徑,長效緩釋、控釋藥物制劑是研究較多的領(lǐng)域,植入劑可避免胰島素口服降解的問題。植入劑的材料為高分子化合物,本課題選用殼聚糖和PLGA作為皮下植入劑的輔料,以制備穩(wěn)定性及生物利用度較高、生物毒性低的胰島素植入劑,對植入劑的處方及制備工藝進行研究,并對該植入劑對糖尿病大鼠的藥效學(xué)進行研究,具體內(nèi)容如下:建立了胰島素外高效液相測定方法,并對方法學(xué)進行驗證。藥物濃度在0.5-10 IU/mL范圍內(nèi),線性曲線關(guān)系A(chǔ)=800396C-12612,R2=0.9999,說明該方法專屬性、線性關(guān)系良好。精密度及穩(wěn)定性RSD值均小于1.7%,本法具有較高的靈敏度和準(zhǔn)確度。建立了胰島素的藥效學(xué)測定方法,使用STZ制備糖尿病大鼠,葡萄糖氧化酶法測定血糖,為后續(xù)確定處方及藥效測定方法提供依據(jù)。溫敏凝膠植入劑的制備及評價,以凝膠溫度和注射的難易程度為評價指標(biāo),確定溫敏凝膠的配制,并考察加入輔料后對其凝膠時間的影響,對凝膠的熱可逆性、穩(wěn)定性和結(jié)構(gòu)進行考察,篩選出最佳凝膠比例,使用高壓勻質(zhì)機制備不同粒徑的胰島素微粒,將微粒載入溫敏凝膠中,皮下注射給藥后測定大鼠血糖,肌肉組織刺激實驗,最后確定優(yōu)化處方為:CS/β-GP+HP-β-CD溫敏凝膠加載胰島素微粒。使用噴霧干燥法制備胰島素微球,制備的微球形態(tài)大小、晶型狀態(tài)、重新分散性載藥量進行研究,微球外觀形態(tài)不規(guī)則,大小不一,載藥量為18.5%(EC1:3)和43%(EC1:1)將胰島素微球載入CS/β-GP+HP-β-CD中進行藥效學(xué)考察,加載胰島素微球的CS/β-GP+HP-β-CD在糖尿病大鼠皮下注射后的低血糖作用持續(xù)72 h,比胰島素注射液和甘精胰島素制劑引起的低血糖效應(yīng)長得多。使用PLGA為載體制備植入片劑,將胰島素加載到PLGA中,加入CMC-Na/HA作為致孔劑,用壓片法制備可植入片劑,通過體內(nèi)和體外實驗對片劑進行篩選,將片劑植入體內(nèi)后,片劑降解明顯,并且PLGA:CMC-Na比例為2.5:1時,糖尿病大鼠皮下植入后的低血糖作用持續(xù)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.
【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943
本文編號：2124068
[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.
【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943
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