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研究生:許文麟
研究生(外文):Wen-Lin Hsu
論文名稱:微針貼片搭載酸鹼敏感性奈米粒子進行葡萄糖調控的皮下胰島素釋放系統開發
論文名稱(外文):Intradermal Glucose-Responsive Insulin Delivery by pH-Sensitive Vesicles incorporated Microneedle Patches
指導教授:楊閎蔚
指導教授(外文):Hung-Wei Yang
學位類別:碩士
校院名稱:國立中山大學
系所名稱:醫學科技研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:中文
論文頁數:96
中文關鍵詞:聚乙烯醇溶解型微針胰島素糖尿病長效血糖控制葡萄糖敏感性奈米粒子
外文關鍵詞:Poly (beta amino ester)InsulinLong-term glycemic controlGlucose-sensitivePolyvinyl alcohol
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  • 被引用被引用:0
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  • 下載下載:14
  • 收藏至我的研究室書目清單書目收藏:0
在 2014 年世界衛生組織的報告中指出,糖尿病已經成為全球四大的非傳染性疾病。在 2014 年的統計資料中,全球已經有 3.87 億的糖尿病患者,而且估計到 2035 年糖尿病患者的人數會成長到 5 億人以上。目前糖尿病的防治上主要是以胰島素的注射為主,但為人所詬病的是注射針及注射筆所造成的疼痛與不便,使得糖尿病的防治上處處摯肘,也間接使得糖尿病患者的血糖控制意願下滑。為了改善這樣的情形,本篇論文的設計中結合了微針藥物輸送系統及葡萄糖敏感性的奈米粒子作為一個新穎的血糖控制系統。
在微針系統的設計上,本篇論文使用了高生物相容性及生物降解性的聚乙烯醇作為微針的主體,這樣的微針系統具有微小化、微侵入性、簡單操作等特點,能夠使糖尿病患者便於攜帶,且不會造成疼痛,也能夠避免因為使用的錯誤而造成傷害。微針的特點可以協助改善患者恐懼針筒的問題,進一步提高患者對於胰島素施打的意願及規律性。
另一方面,本篇論文所設計的葡萄糖敏感性奈米粒子可以延長血糖控制的時間;藉由血糖的濃度來調整奈米粒子中胰島素的釋放,這樣的方式可以控制胰島素不至於過度釋放,也可以延長奈米粒子作用的時間來減少患者的使用次數,進而提高方便性。最後在實驗中,也會針對安全性進行分析,確認本篇論文設計的微針與奈米粒子輸送系統對生物體不會造成顯著影響或危害,提高本系統應用於臨床使用的可能性。
Diabetes mellitus has become a serious non-communicable disease in the World. As of 2014, Diabetes mellitus affects about 387 million people and the number is estimated to increase to over then 500 million by 2035. Typically, subcutaneous insulin injection is a key of glycemic control but it is also inconvenient and painful. These weakness lie bad blood glucose monitoring and disseminating diabetes complications. To improve the weakness, inhaled and oral insulin delivery has been introduced in the early years. However, they cannot be an effective insulin delivery system in clinical diabetes care now due to their side effects, high cost as well as low bioavailability. Therefore, we designed a new intradermal drug delivery system, which combines microneedle (MN) patch and nanoparticles, as a novel long-term glycemic control strategy. Microneedles, a pain-free and minimally invasive drug delivery system made from biocompatible and biodegradable polymer (i.e., polyvinyl alcohol or polyvinylpyrrolidone), is portable to improve the poor patient compliance of glycemic control for diabetes homecare. Furthermore, we also designed a glucose-sensitive nanoparticles to achieve the long-term glycemic control and avoid the hypoglycemia risk. This smart insulin patch offers a clinical opportunity for closed-loop delivery of insulin in a long-term glycemic control, pain-free, and safe manner.
摘要 I
Abstract II
目錄 III
圖次 VI
表次 VIII
第一章 介紹 1
1.1 糖尿病 1
1.1.1 糖尿病疾病概況 1
1.1.2 糖尿病盛行率 2
1.1.3 糖尿病的死亡率 2
1.1.4 糖尿病造成的經濟損失 3
1.1.5 糖尿病的分類 3
1.1.6 糖尿病病因 6
1.1.7 糖尿病的症狀 7
1.1.8 糖尿病的治療 8
1.2 糖尿病用藥與給藥途徑 9
1.2.1 口服給藥 9
1.2.2 吸入劑(經肺)給藥 11
1.2.3 注射給藥 11
(1) 胰島素 12
I. 人胰島素 12
II. 胰島素類似物 13
(2) 昇糖素胜肽類似物 (GLP – 1) 14
1.2.4 胰島素幫浦 15
1.2.5 經皮輸送給藥 15
1.3微針藥物輸送系統 16
1.3.1 皮膚屏障 16
1.3.2 微針貼片 17
1.3.3 微針胰島素輸送 20
1.4 胰島素的緩效釋放 22
1.5 研究動機與目的 25
第二章 實驗材料與方法 27
2.1 實驗材料 27
2.1.1 實驗藥品 27
2.1.2 實驗耗材 28
2.1.3 實驗動物 28
2.2 實驗儀器 29
2.3 研究方法 31
2.3.1 葡萄糖敏感性奈米粒子製作 31
2.3.2 葡萄糖敏感性奈米粒子物化性質分析 31
2.3.3 葡萄糖敏感性奈米粒子包覆葡萄糖氧化酵素包覆率分析 34
2.3.4 聚乙烯醇胰島素微針與長效葡萄糖敏感性微針製備 36
2.3.5 長效葡萄糖敏感性胰島素微針物化性質分析 38
2.3.6 微針胰島素包覆率分析 39
2.3.7 微針穿刺/溶解能力分析 40
2.3.8 活體氯化鋅胰島素有效性分析 42
2.3.9 長效血糖控制實驗 45
2.3.10 活體安全性測試 46
第三章 結果與討論 48
3.1 葡萄糖敏感性奈米粒子製作與鑑定 48
3.1.1 合成 Insulin-FITC 48
3.1.2 葡萄糖敏感性奈米粒子製作 49
3.1.3 葡萄糖敏感性奈米粒子物化性質分析 50
3.1.4 葡萄糖敏感性奈米粒子對葡萄糖氧化酵素包覆率分析 54
3.2 長效葡萄糖敏感性胰島素微針及胰島素微米微針製作與鑑定 56
3.2.1 胰島素微針包覆率測試 56
3.2.2 長效葡萄糖敏感性微針影像分析 58
3.2.3 機械性質及溶解試驗 60
3.2.4 體外皮下藥物分布分析 65
3.2.5 體外豬皮穿刺 3 D 結構重組影像分析 67
3.3 動物實驗 68
3.3.1 活體胰島素劑量測試 68
3.3.2 活體氯化鋅胰島素有效性測試 69
3.3.3 胰島素微針活體有效性實驗 70
3.3.4 長效葡萄糖敏感性胰島素微針活體試驗 72
3.4 安全性實驗 74
3.4.1 活體微針傷口癒合實驗 74
3.4.2 活體皮膚刺激性評估 74
3.4.3 組織切片與蘇木精-伊紅染色 76
第四章 結論 78
參考文獻 80
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