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系統識別號 U0026-1808201411120600
論文名稱(中文) 貼片可溶式鑲嵌型幾丁聚醣微針於經皮緩釋荷爾蒙之應用
論文名稱(英文) Embeddable Chitosan Microneedles with Patch-dissolvable Design for Sustained Transdermal Delivery of Hormone
校院名稱 成功大學
系所名稱(中) 化學工程學系
系所名稱(英) Department of Chemical Engineering
學年度 102
學期 2
出版年 103
研究生(中文) 陳淑媛
研究生(英文) Shu-Yuan Chen
學號 n36011586
學位類別 碩士
語文別 中文
論文頁數 70頁
口試委員 指導教授-陳美瑾
口試委員-鄭瑞棠
口試委員-蔡育賢
口試委員-陳毓宏
口試委員-林宥欣
中文關鍵字 幾丁聚醣  鑲嵌式微針  經皮緩釋  荷爾蒙治療 
英文關鍵字 chitosan  embeddable  microneedles  transdermal sustained delivery  hormone therapy 
學科別分類
中文摘要 本論文乃研發一鑲嵌式緩釋荷爾蒙新型微針系統,將生物可降解之幾丁聚醣(chitosan, CS)微針與水溶性聚乙烯吡咯烷酮(polyvinylpyrrolidone, PVP)和聚乙烯醇(polyvinyl alcohol, PVA)支撐陣列組合。此微針能在穿刺皮膚後,藉由體內組織液將後端支撐陣列溶解,僅留幾丁聚醣針體於皮膚中,緩慢而持續地釋放荷爾蒙;為改善本實驗室前一代幾丁聚醣微針在製程中大量損耗藥物之問題,本研究對製程進行改良,使割除之含藥幾丁聚醣貼片可回收再利用,達到100%藥物可利用率。由體外豬皮及體內大鼠穿刺試驗證實,所製備之微針皆具有足夠之機械強度可刺穿角質層,並讓微針鑲嵌於真皮層上方,深度約750微米。以標的螢光之牛血清蛋白作為model drug進行體外藥物釋放實驗,第七天時僅釋放約16%的藥量,證實幾丁聚醣微針可緩釋蛋白質藥物至少達七天以上。體內降解與釋放實驗亦證實,微針可於皮膚內逐漸降解並釋放藥物長達28天。將黃體激素釋放激素(luteinizing hormone-releasing hormone, LHRH)包覆於微針中,並儲存於室溫下一個月,經圓二色光譜儀證實其二級結構並無明顯改變。然而,人類生長賀爾蒙(human growth hormone, hGH)之二級結構卻有明顯地改變,將包覆hGH之微針應用於大鼠,僅能於第一天偵測到血中荷爾蒙含量,推測是因hGH在微針包覆過程中已造成蛋白質結構上的改變,進而影響其活性。未來將探討由幾丁聚醣微針釋放之LHRH之生物活性,評估其臨床應用之可行性。
英文摘要 This study introduces a microneedle system, composed of embeddable chitosan microneedles with a dissolvable poly(vinyl pyrrolidone)/poly(vinyl alcohol) (PVP/PVA) supporting array, for complete and sustained delivery of encapsulated hormone to the skin. In vitro and in vivo skin insertion test demonstrated that the obtained microneedles can penetrate through the stratum corneum. In vivo degradation and drug release study also confirmed that chitosan microneedles gradually degraded in the skin and provided a sustained release of BSA for at least 28 days.This results suggest that chitosan microneedles are a promising depot for sustained delivery for protein.
論文目次 目錄
摘要 Ⅰ
Abstract Ⅱ
致謝 Ⅷ
目錄 Ⅸ
表目錄 XI
圖目錄 XI
第一章 緒論 1
1.1緩釋荷爾蒙 1
1.1.1 緩釋人類生長荷爾蒙 1
1.1.2 緩釋黃體激素釋放激素 4
1.2 經皮藥物傳輸與微針貼片 8
1.2.1 經皮藥物傳輸 8
1.3 材料 13
1.3.1 幾丁聚醣(chitosan) 14
1.3.2 海藻糖(trehalose) 14
1.3.3 聚乙烯吡咯烷酮(polyvinylpyrrolidone, PVP) 15
1.3.4 聚乙烯醇(Polyvinyl alcohol, PVA) 16
1.4 研究目的 17
第二章 實驗材料與方法 20
2.1 實驗藥品、耗材與動物 20
2.2 儀器設備 22
2.3 鑲嵌式微針貼片 24
2.3.1 幾丁聚醣微針貼片之製備 24
2.3.2 微針穿刺能力測試 27
2.4包覆蛋白質藥物之幾丁聚醣微針貼片 28
2.4.1 包覆蛋白質藥物之微針定量檢測分析 28
2.4.2 包覆螢光蛋白質藥物微針貼片之製備 29
2.4.3 體外蛋白質藥物釋放試驗 29
2.4.4 體內蛋白質藥物釋放測試 30
2.4.5 體內微針降解及藥物釋放測試 31
2.5包覆荷爾蒙之鑲嵌式微針貼片 31
2.5.1 蛋白質之二結結構完整性測試 31
2.5.2 包覆人類生長荷爾蒙微針進行活體藥物學測試 33
第三章 結果與討論 34
3.1 貼片可回收再生之鑲嵌式微針貼片 34
3.1.1 鑲嵌式幾丁聚醣微針 34
3.1.2 貼片回溶重新製做之幾丁聚醣微針 35
3.1.3 微針穿刺能力分析 36
3.2包覆牛血清白蛋白之鑲嵌式微針貼片 37
3.2.1包覆蛋白質藥物之微針定量檢測分析 37
3.2.2包覆螢光藥物之幾丁聚醣微針 38
3.2.3 體外藥物釋放情形 40
3.2.4 體內藥物釋放情形 40
3.2.5 體內微針貼片降解情形 43
3.3包覆荷爾蒙之鑲嵌式微針貼片 53
3.3.1人類生長荷爾蒙之完整性測試 53
3.3.2黃體激素釋放激素之完整性測試 54
3.3.3包覆人類生長荷爾蒙微針進行活體藥物學測試 54
第四章 結論 57
參考文獻 59
表目錄
表1-1、LHRH臨床用藥之序列比較[32] 7
表3-1 幾丁聚醣微針之蛋白質藥物包覆量 37
圖目錄
圖1-1 人類生長荷蒙 : (a) 3-D結構;(b)分泌機制[1,2] 1
圖1-2緩釋人類生長荷爾蒙種類 2
圖1-3 生物可降解的植入物:(a)植入物大小比較圖,(b)注射位置及方式[10,12] 3
圖1-4黃體激素釋放激素: (a)結構示;(b)分泌機制[16] 4
圖1-5 (a)前列腺位置;(b)正常前列腺與前列腺癌比較圖[23] 5
圖1-6 皮膚構造示意圖 9
圖1-7 各種材料之微針[46] 10
圖1-8 第一代幾丁聚醣微針: (a)幾丁聚醣微針影像圖;(b)組織切片圖。 12
圖1-9 第二代幾丁聚醣微針: (a)幾丁聚醣微針影像圖;(b)組織切片圖。 12
圖1-10 第三代幾丁聚醣微針: (a)幾丁聚醣微針影像圖;(b)組織切片圖。 13
圖1-11 幾丁聚醣結構式 14
圖1-12 海藻糖結構式 15
圖1-13 聚乙烯吡咯烷酮結構式 16
圖1-14 聚乙烯醇結構式 16
圖1-15鑲嵌式幾丁聚醣微針示意圖 17
圖1-16 第三代幾丁聚醣微針製程示意圖 18
圖1-17 實驗架構 19
圖2-1 不鏽鋼主結構:(a)金字塔微針;(b)支撐軸 24
圖2-2 可回收之幾丁聚醣微針製備過程示意圖 26
圖2-3 體外穿刺實驗流程示意圖 27
圖2-4 體內穿刺實驗流程示意圖 28
圖2-5體外蛋白質藥物釋放之前處理流程圖 30
圖2-6 非侵入式活體影像(IVIS)分析 31
圖3-1 可鑲嵌式幾丁聚醣微針:(a)支撐軸陣列光學顯微影像;(b)五倍放大後影像;(c)微針主體與支撐軸黏合後之光學顯微影像;(b)五倍放大後影像 34
圖3-2側面圖 : (a)回收再生之可鑲嵌幾丁聚醣微針;(b) 可鑲嵌幾丁聚醣微針;正面圖:(c) 回收再生之可鑲嵌幾丁聚醣微針;(d) 可鑲嵌幾丁聚醣微針。 35
圖3-3豬皮體外穿刺結果: (a)可鑲嵌幾丁聚醣微針穿刺後的豬皮;(b)回收再生之可鑲嵌幾丁聚醣微針穿刺後的豬皮;(c)可鑲嵌幾丁聚醣微針穿刺後的豬皮組織切片;(d)回收再生之可鑲嵌幾丁聚醣微針穿刺後的豬皮組織切片。 36
圖3-4 接枝FITC之幾丁聚醣微針對大鼠進行體內穿刺之結果:(a)穿刺鼠皮之陣列;(b)可見光影像;(c)螢光影像。 37
圖3-5 包覆CF594-BSA之貼片可溶式幾丁聚醣微針:(a)光學顯微影像;(b)1.5倍放大後之光學顯微影像;(c)螢光影像 38
圖3-6 包覆TAMRA-LHRH之貼片可溶式幾丁聚醣微針:(a)光學顯微影像;(b)5倍放大後之光學顯微影像;(c)螢光影像 39
圖3-7 包覆CF594-BSA幾丁聚醣微針(含10%海藻糖)之體外藥物釋放情形 40
圖3-8 非侵入式活體影像(IVIS)分析體內BSA釋放情形:(a)螢光強度定量結果;(b)0天時活體螢光影像全景圖;(c)含5%海藻糖之幾丁聚醣微針穿刺後不同時間下之螢光影像;(d)含10%海藻糖之幾丁聚醣微針穿刺後不同時間下之螢光影像。 41
圖3-9 非侵入式活體影像(IVIS)分析體內LHRH釋放情形:(a)螢光強度定量結果;(b)22mPa.s幾丁聚醣微針穿刺後不同時間下之螢光影像。 42
圖3-10多光子共軛焦顯微影像系統分析包覆CF594-BSA幾丁聚醣微針穿刺大鼠背部後第0天,不同z軸深度之x-y平面螢光影像及3D影像圖。 44
圖3-11多光子共軛焦顯微影像系統分析包覆CF594-BSA幾丁聚醣微針穿刺大鼠背部後第7天,不同z軸深度之x-y平面螢光影像及3D影像圖。 45
圖3-12多光子共軛焦顯微影像系統分析包覆CF594-BSA幾丁聚醣微針穿刺大鼠背部後第14天,不同z軸深度之x-y平面螢光影像及3D影像圖。 46
圖3-13 多光子共軛焦顯微影像系統分析包覆CF594-BSA幾丁聚醣微針穿刺大鼠背部後第21天,不同z軸深度之x-y平面螢光影像及3D影像圖。 47
圖3-14多光子共軛焦顯微影像系統分析包覆CF594-BSA幾丁聚醣微針穿刺大鼠背部後第28天,不同z軸深度之x-y平面螢光影像及3D影像圖。 48
圖3-15 幾丁聚醣微針鑲嵌於活體SD大鼠皮膚內緩慢降解之組織切片圖。 50
圖3-16 多光子共軛焦顯微影像系統分析包覆TAMRA-LHRH幾丁聚醣微針穿刺大鼠背部後於不同時間,不同z軸深度之x-y 3D影像圖。 52
圖3-17 人類生長荷爾蒙之圓二色光圖譜 53
圖3-18 黃體激素釋放激素之圓二色光圖譜 54
圖3-19 人類生長荷爾蒙之藥物動力學試驗 55
圖3-20幾丁聚醣微針包覆人類生長荷爾蒙之活體藥物釋放曲線 56
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