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研究生:林宜美
研究生(外文):Yi-Mei Lin
論文名稱:幾丁質摻合聚乳酸酯微粒於藥物釋放系統之研究
論文名稱(外文):Chitin/PLGA blend microspheres as a biodegradable drug delivery system: Phase separation, degradation and release behavior
指導教授:徐新興
指導教授(外文):Shin-Shing Shyu
學位類別:碩士
校院名稱:國立中央大學
系所名稱:化學工程與材料工程研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:99
中文關鍵詞:乳酸羥基乙酸共聚合物聚乳酸酯幾丁質藥物釋放
外文關鍵詞:Poly(DPLGAchitinL-lactide-co-glycolide)drug-release
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中 文 摘要
本研究主要的目的是利用溼式相轉化製程來製備幾丁質(chitin)摻合聚乳酸酯(PLGA)之藥物載體微小球,並以改變重量比例、水相溫度及聚乳酸酯中乳酸/羥基乙酸共聚比例不同等條件來形成不同系列的微小球。本研究藉由水含量實驗掃描式電子顯微鏡(SEM) 、示差掃描熱卡計(DSC) 、X-ray粉末繞射儀(XRD) 、霍氏紅外線光譜儀(FTIR)的分析以及來探討此微小球的基本物性及表面結構型態,並經由體外裂解實驗來觀察此載體裂解的速率與行為。
由SEM觀察可得,幾丁質/聚乳酸酯摻合微小球中有許多聚乳酸酯微小顆粒散佈在幾丁質基質中,顯示摻合微小球中幾丁質與聚乳酸酯呈現微相分離的情形。當改變製程中水相溫度時,聚乳酸酯在微小球中均勻分散的程度會隨著溫度的增加而增加,顯示提高製程溫度可增加幾丁質與聚乳酸酯的摻合性。在體外裂解實驗中,微小球的重量損失隨著幾丁質含量增加以及聚乳酸酯中羥基乙酸比例增加而增加。根據SEM和DSC的分析結果可知,幾丁質/聚乳酸酯摻合微小球的裂解作用是藉由幾丁質表面的剝蝕效應和聚乳酸酯的整體溶蝕水解而進行。幾丁質/聚乳酸酯以不同重量比摻合的微小球包覆抗癌藥物進行藥物釋放,其釋放曲線呈現兩階段的釋放模式,初期為快速且大量的釋放,且隨著幾丁質含量增加而釋放速率增加,後期釋放速率緩慢且可延續釋放至7天以上。不同溫度製程系列和不同共聚比例之聚乳酸酯系列的幾丁質/聚乳酸酯摻合微小球包覆蛋白質進行釋放,隨著其釋放曲線也呈現兩階段釋放行為,而初期為緩慢的釋放,且隨著製程溫度升高其釋放速率較快,而聚乳酸酯共聚合物比例也會影響蛋白質的釋放速率,後期則為大量且快速的釋放,整體的釋放情形可持續釋放至14天以上。


Abstract
A novel chitin-based microsphere was developed for drug-delivery purpose in the present study. These biodegradable microspheres were prepared by directly blending chitin with poly(D,L-lactide-co-glycolide ) (PLGA) in DMAc-LiCl solution, followed by being coagulated in water via wet phase inversion. Three condition of the experiment were employed:chitin has blended with different contents of PLGA, and blending solution has been coagulated in water with different temperature, and chitin has blended with different copolymer composition ratio of PLGA. The physicochemical properties of chitin/PLGA blend microspheres were studied by water uptake capacity, in vitro degradation test, SEM, DSC, XRD, and FTIR.
SEM micrography of the blend microsphere showed that there are numerous PLGA particulates homogeneously dispersed in chitin matrix, suggesting the occurrence of obvious phase separation from the blended chitin and PLGA phase. The distribution of PLGA in chitin matrix has been improved by higher water temperature. From SEM observed, the well-distributed properties of PLGA in chitin/PLGA microspheres were increased with higher water temperature. Weight loss of the chitin/PLGA blend microsphere increases with the increase of chitin content in the microsphere, and also increases with the increase of glycolide composition ratio of PLGA. Degradation of the chitin/PLGA blend microsphere depends on the surface erosion of chitin phase and bulk hydrolysis of PLGA phase, according to the examinations of SEM and DSC studies. Two-phase drug release model is observed from the release of chlorambucil from chitin/PLGA blend microspheres. The initial stage of fast drug-release rate increases with the increased chitin content, the followed stage of slow release is sustained for several days. However, the release of Albumin from chitin/PLGA blend microspheres in different water temperature series and different copolymer ratio of PLGA series also have two-stage release model, but the initial stage has slowly release rate that increases with raising water temperature during preparing process, and the different copolymer composition ratio of PLGA also has effect on the protein release rate; the followed stage has fast release rate and sustained for 14 days.


目 錄
目錄……………………………………………………………………..Ⅰ
表目錄……………………………………………………………….….Ⅲ
圖目錄……………………………………………………………….….Ⅳ
中文摘要…………………………………………………………….….Ⅷ
英文摘要…………………………………………………………….….Ⅸ
第一章緒論…………………………………………………………..1
第二章文獻回顧……………………………………………………..3
2.1 藥物控制釋放…………………………………………………….3
2.1.1 微粒包覆技術………………………………………………..7
2.2 幾丁質……………………………………………………………..7
2.2.1 幾丁質的製備………………………………………………..10
2.2.2 幾丁質的物理與化學性質…………………………………..10
2.2.3 幾丁質在生醫材料上的特性及應用………………………..11
2.3 聚乳酸(PLA)與乳酸/羥基乙酸共聚合高分子(PLGA)………….14
2.3.1 PLA與PLGA的合成………………………………………..18
2.3.2 PLA與PLGA的物理性質與水解作用………………………18
2.3.3 PLA與PLGA之生物相容性………………………………….23
2.3.4 PLA與PLGA生醫材料上之研究與應用…………………….23
2.4 抗癌樂物chlorambucil……………………………………………..24
2.5 牛血清白蛋白(BSA)……………………………………………….25
2.6 濕式相轉化法……………………………………………………...26
第三章實驗……………………………………………………………30
3.1 實驗目的…………………………………………………………30
3.2 實驗藥品…………………………………………………………..30
3.3 實驗儀器…………………………………………………………..31
3.4實驗方法……………………………………………………………31
3.4.1 Chitin與PLGA摻合微小球之製備…………………………..33
3.4.2 包覆藥物之Chitin/PLGA摻合微小球之製備……………….34
3.4.3 掃描式電子顯微鏡(SEM)表面結構觀察…………………….34
3.4.4 紅外線光譜分析(FTIR)實驗………………………………….35
3.4.5 微差掃描式熱分析(DSC)實驗………………………………..35
3.4.6 X-ray光譜分析(XRD)實驗……………………………………35
3.4.7 水含量實驗……………………………………………………35
3.4.8 體外裂解(in vitro)實驗……………………………………….36
3.4.9 藥物釋放實驗…………………………………………………36
3.4.10 蛋白質釋放實驗……………………………………………..36
第四章結果與討論……………………………………………………37
4.1 SEM表面結構觀察分析…………………………………………..37
4.2 DSC分析…………………………………………………………...49
4.3 XRD分析…………………………………………………………..55
4.4 FTIR分析…………………………………………………………..60
4.5 水含量分析………………………………………………………..64
4.6 體外裂解實驗分析………………………………………………66
4.7 藥物釋放分析……………………………………………………77
4.8 蛋白質釋放分析…………………………………………………..83
第五章結論……………………………………………………………95
參考文獻 ………………………………………………………………97


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