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研究生:吳永志
論文名稱:水溶性幾丁聚醣衍生物的合成及其水膠的製備
論文名稱(外文):Synthesis of water-soluble chitosan derivatives and preparation of their hydrogels
指導教授:宋信文
學位類別:碩士
校院名稱:國立清華大學
系所名稱:化學工程學系
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:85
中文關鍵詞:水膠幾丁聚醣pH sensitivity藥物釋放
外文關鍵詞:hydrogelchitosandrug delievery system
相關次數:
  • 被引用被引用:1
  • 點閱點閱:253
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:3
水膠是指具有3-D 網狀結構之高分子,且具有在水中膨潤但不溶解的性質。近幾年來水膠的研究重點著重於功能型水膠之設計,此種水膠會隨著外界環境變化而產生相對應的應答行為使得水膠產生形態上的改變。而藥物釋放所訴求的目的不外乎下列幾點︰增加藥效或延長藥物作用時間、降低藥物副作用、適時、適量將藥物帶到標的部位。水膠具有上述的功能,藉由其在不同的生理環境下產生收縮或膨潤的變化,進而達到控制釋放、延長藥效及藥物標的的作用,因此可將水膠應用在藥物釋放系統。
以幾丁聚醣做為藥物釋放之載體其適用範圍是以酸性環境為主。因此為了改變幾丁聚醣的酸鹼應答行為,我們利用化學方法做一修飾接上甲基(carboxymethyl group),使其具有在酸性條件下收縮鹼性環境下膨潤的性質,依此計畫,可得到三種不同接枝位置的水溶性產物:N,O-carboxymethyl chitosan (NOCC)、N-carboxymethyl chitosan (NCC)、O-carboxymethyl chitosan (OCC)。經過實驗分析結果來看,經由FOURIER-TRANSFORM INFRARED SPECTROMETER (FT-IR)的分析可證明幾丁聚醣在經由三種不同化學方法後在其鏈上是有接上甲基(carboxymethyl group),而在接枝的位置上經由NMR證明NOCC其胺基與第6個碳上的氧皆有受到化學修飾,且其接枝比分別為13.0 %及10.5 %。在體外抗酵素分解方面,幾丁聚醣分子鏈上經由化學修飾而導入carboxymethyl group,經由ninhydrin assay的分析,可加速被Lysozyme分解的速度。
在水膠性質測試方面,單獨使用NOCC以GP製成水膠,由於分子上的胺基在酸性下會質子化而帶正電,因此造成在測試其酸鹼可逆性質時,當NOCC水膠從酸性環境移入中性環境下帶正電的胺基會與帶負電的基形成吸引力,因而產生收縮現象。所以我們將胺基乙醯化成乙醯胺基以改善收縮現象,然而乙醯化後的水膠仍有兩個問題需要去改善,第一是在酸性環境下起始膨潤過高;第二是在酸性及鹼性環境下的膨潤差異度過低,因此分別以酸處理及加入alginate來加以改善。經實驗證明,經由加入alginate及乙醯化和醋酸處理後,NOCC/alginate GP交聯水膠是適用於intestine site-specific drug delivery system。
經由三種不同交聯結構所製備的NOCC/alginate水膠,GP是以胺基為交聯對象,因此NOCC分子會被交聯而形成網目結構,且alginate分子穿插於NOCC的網目結構中,因而形成semi-IPN (semi-interpenetrating polymer network)構造。Glutaraldehyde (GA)的交聯結構經由文獻及本實驗的FT-IR結果說明,GA是會與NOCC及alginate分子上的醇基(-OH)產生交聯反應。離子交聯方面,經由FT-IR證明解離帶負電的基會被鈣離子所交聯。
在藥物包覆及釋放方面, GP交聯水膠包覆率為100%;離子交聯水膠包覆率約為92%,而GA交聯水膠則因為交聯液為強酸環境(pH 0.46),因此造成蛋白質結構denature,所以造成測不到其濃度。雖然GP交聯水膠發現交聯劑對蛋白質藥物有所影響,但由其釋放行為來看是有達到腸部標的釋放的目標,所以GP交聯水膠也可適用於其他非蛋白質藥物。另一方面,亦可使用不同的藥物包覆方式如吸附法,應可以改善GP對於蛋白質的影響。同樣地,離子交聯水膠亦有達到腸部標的釋放的目標,且其溫和的反應環境,因此此種水膠是一較理想的蛋白質藥物載體。

摘要-----------------------------------------------------------I
目錄----------------------------------------------------------IV
圖索引-------------------------------------------------------VII
表索引---------------------------------------------------------X
第一章 緒論
1-1 水膠 1
1-2 幾丁聚醣 1
1-3 研究動機與目的 3
第二章 水溶性幾丁聚醣衍生物的合成
2-1 研究目的 11
2-2 幾丁聚醣衍生物的製備 11
2-2-1 幾丁聚醣原料 11
2-2-2 N,O-carboxymethyl chitosan (NOCC)的製備 11
2-2-3 N,O-carboxymethyl chitosan (NCC)的製備 11
2-2-4 O-carboxymethyl chitosan (OCC)的製備 12
2-3 定性分析 15
2-3-1 傅立葉轉換紅外線光譜分析 15
2-3-2 核磁共振分析(NMR) 15
2-4 體外抗酵素分解 15
2-5 實驗結果與討論 18
2-5-1 NOCC之FT-IR分析 18
2-5-2 NCC之FT-IR分析 18
2-5-3 OCC之FT-IR分析 20
2-5-4 NOCC核磁共振分析(NMR) 21
2-5-4-1 定性分析 21
2-5-4-2 定量分析 21
2-5-5 體外抗酵素分解 24
2-6 結論 25
第三章 NOCC水膠製備
3-1 研究目的 26
3-2 NOCC水膠的製備 26
3-3 膨潤性質測試 27
3-4 酸鹼可逆性質 28
3-5 NOCC/alginate水膠之製備 29
3-6 實驗結果與討論 30
3-6-1 膨潤性質測試 30
3-6-2 酸鹼可逆性質 30
3-7 結論 39
第四章 不同交聯結構之水膠製備及蛋白質藥物包覆及釋放
4-1 研究目的 40
4-2 不同交聯結構之水膠製備 40
4-2-1 胺基交聯(GP交聯之水膠) 40
4-2-2 醛醇反應交聯(GA交聯之水膠) 40
4-2-3 離子交聯 41
4-3 不同交聯結構之水膠其酸鹼可逆性質測試 42
4-4 水膠交聯結構分析 43
4-5 蛋白質藥物包覆 44
4-5-1 GP交聯之水膠包覆蛋白質 44
4-5-2 GA交聯之水膠包覆蛋白質 44
4-5-3 離子交聯交聯之水膠包覆蛋白質 46
4-6 蛋白質定量(Bradford Method) 47
4-7 包覆率分析 47
4-8 不同交聯結構水膠之藥物釋放實驗 48
4-9 結果與討論 50
4-9-1 交聯結構分析 50
● GP交聯結構分析(胺基交聯) 50
● GA交聯結構分析(醛醇反應交聯) 50
● Calcium交聯結構分析(離子交聯) 54
4-9-2 不同交聯結構之水膠其酸鹼可逆性質測試 55
4-9-3 包覆率分析 56
4-9-4 不同交聯結構之水膠之藥物釋放行為 57
● GP交聯水膠 57
● Calcium交聯水膠 61
● in pH 7.4溶離液 63
● in pH 1.2溶離液 63
4-10 結論 64

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