本文選題：SAIB載藥貯庫 + 體外釋放��； 參考：《河北大學(xué)》2017年碩士論文

【摘要】：乙酸異丁酸蔗糖酯(sucrose acetate isobutyrate,SAIB)能溶解于具有生物相容性的有機(jī)溶劑中,只需很少的溶劑量就可將SAIB溶液的黏度降低至適于注射的范圍。在注射給藥后,溶劑與水進(jìn)行互換,蔗糖酯在注射部位生成沉淀,藥物則被固態(tài)基質(zhì)包裹,經(jīng)溶出、擴(kuò)散等緩慢釋放。聚乳酸(polylactic acid,PLA)是以淀粉為原料發(fā)酵生成乳酸,再經(jīng)化學(xué)聚合而成的聚合物。PLA可在人體內(nèi)降解生成乳酸,最終代謝為水和二氧化碳。聚乳酸具有良好的生物相容性,美國(guó)FDA已批準(zhǔn)聚乳酸用作醫(yī)用和緩控釋藥物的材料。胰島素(INS)臨床上用于Ⅰ型糖尿病、部分Ⅱ型糖尿病、妊娠糖尿病及各種繼發(fā)性糖尿病的治療,由于胰島素直接口服無治療效果,目前主要依靠皮下注射途徑給藥。為了降低糖尿病人因頻繁注射胰島素所帶來的痛苦,減少給藥頻率,本論文選用PLA和SAIB為載藥基質(zhì),構(gòu)建了兩種新型的胰島素載藥系統(tǒng):胰島素-SAIB載藥貯庫以及胰島素PLA植入片,以期延長(zhǎng)胰島素的作用時(shí)間,減少血糖波動(dòng),提高患者順應(yīng)性。本文建立了胰島素-SAIB載藥貯庫以及胰島素PLA植入片的體外高效液相色譜分析方法,方法學(xué)考察結(jié)果均符合相關(guān)規(guī)定�？疾炝薙AIB/無水乙醇溶液系統(tǒng)的流變學(xué)性質(zhì),20%(w/w)無水乙醇的SAIB溶液系統(tǒng)的黏度為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圍內(nèi)。選用高壓均質(zhì)法及凍干法制備了不同均質(zhì)次數(shù)的胰島素凍干粉末,采用復(fù)乳溶劑揮發(fā)法制備了INS-PLA載藥微球。使用掃描電子顯微鏡、傅里葉變換紅外光譜儀、差示掃描量熱儀、X射線粉末衍射儀對(duì)制備的微球進(jìn)行表征,并測(cè)定微球的包封率及載藥量。結(jié)果表明微球表面光滑、球形度良好,胰島素均勻地分布在聚乳酸微球中。分別以不同均質(zhì)次數(shù)的胰島素凍干粉末、胰島素PLA微球?yàn)橹饕幬?SAIB為基質(zhì),無水乙醇為溶劑,制備胰島素-SAIB載藥貯庫。進(jìn)行了胰島素PLA微球-SAIB載藥貯庫的體外釋放實(shí)驗(yàn),釋放12小時(shí),胰島素的累積釋放量達(dá)到34.5±2.5%,隨后釋放速率放緩,96小時(shí)后,胰島素的累積釋放量達(dá)到72.1±2.9%。制備了胰島素PLA植入片,通過體外的分散性實(shí)驗(yàn)及皮下埋植實(shí)驗(yàn)篩選出了兩種親水性輔料:泊洛沙姆188,泊洛沙姆407。體外釋放性實(shí)驗(yàn)表明,植入片中泊洛沙姆與PLA的比例及不同型號(hào)的泊洛沙姆共同造成了各植入片在釋放速度上的差別。12小時(shí)后,各處方下植入片的累積釋藥量達(dá)到70.6±1.8%?84.8±1.6%。掃描電鏡顯示了皮下植入后植入片產(chǎn)生的孔洞結(jié)構(gòu),這是由于泊洛沙姆188和泊洛沙姆407的水溶性良好,能夠持續(xù)溶解,可在植入片內(nèi)外形成濃度梯度,在向體液釋放過程中,形成了微小孔道。植入片表面和淺表層的胰島素通過擴(kuò)散作用直接進(jìn)入釋放介質(zhì)中,植入片內(nèi)部的胰島素通過PLA基質(zhì)中泊洛沙姆溶蝕出的孔道向外擴(kuò)散。以Wistar雄性大鼠為實(shí)驗(yàn)動(dòng)物,選用鏈脲佐菌素為動(dòng)物糖尿病誘發(fā)劑,制備了Ⅱ型糖尿病大鼠模型,分別對(duì)胰島素-SAIB載藥貯庫以及胰島素PLA植入片的體內(nèi)藥效學(xué)進(jìn)行了研究。實(shí)驗(yàn)數(shù)據(jù)表明胰島素-SAIB載藥貯庫及胰島素PLA植入片均有較好的降血糖作用。同樣劑量(10 IU/kg)下,前4 h載有胰島素PLA微球的SAIB貯庫系統(tǒng)與胰島素PLA植入片都有突釋現(xiàn)象發(fā)生,但隨后都穩(wěn)定在一個(gè)平臺(tái)期。載有胰島素PLA微球的SAIB貯庫系統(tǒng)的有效作用時(shí)間約為120 h。胰島素PLA植入片的有效作用時(shí)間約為84 h。肌肉刺激性實(shí)驗(yàn)結(jié)果表明胰島素-SAIB貯庫的肌肉刺激性小,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.

【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R943;R965

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