臺灣博碩士論文加值系統

中文摘要
本研究主要為合成表面帶有螢光標記之智慧型藥物載體顆粒,以Dioctadecylamine-501 (DODA -501)作為疏水性部位，異丙基丙烯醯胺 (N-isopropylacrylamide, NIPAAm)，丙烯酸(Acrylic acid, AAc)增加其親水性。因本實驗所製備之奈米顆粒由NIPAAm與AAc聚合而成，故具有溫度與酸鹼值感應性。其粒徑約為94-200 nm，且粒徑受DODA-501含量、環境中溫度或酸鹼值不同所影響，證實其具有溫度與酸鹼值感應性。並由Confocal Laser Scanning Microscopy (CLSM)之觀察實驗證明其可將模擬藥物包埋於顆粒內部而非吸附於表面，並證明具表面螢光標定能力。而藥物包埋與釋放測試實驗中，可證實本實驗所製備出之奈米顆粒具有包埋胰島素之能力，且藥物之釋放現象受所處環境之酸鹼值調控，於模擬胃液環境可對包埋之胰島素進行緩釋，使其不受胃酸破壞，而於模擬腸液時較迅速地使胰島素進行釋放。而穩定性試驗證實此奈米顆粒具有良好之保存穩定性。綜合以上結果可證實本研究製備之奈米顆粒適合作為口服藥物之傳輸應用上。

ABSTRACT
In this work, fluorescently labeled smart micelle copolymers which consist of Dioctadecylamine-501 (DODA-501) as the hydrophobic segment, N-isopropylacrylamide (NIPAAm) as well as acrylic acid (AAc) as the hydrophilic segments were prepared. These micelles showed both thermo- and pH-sensitive properties due to the nature properties of NIPAAm and AAc, respectively. The particle size of the prepared micelles ranged from 94～200 nm and was found to increase with DODA-501 concentration. The size of particles varied in different pH mediums or different temperatures suggesting these micelles were pH- and thermo- sensitive. The image of confocal laser scanning microscopy (CLSM) illustrates these micelles had the ability to encapsulate rhodamine solution. From CLSM observation, fluorescein isothiocyanate (FITC) expression was found on the surface of micelles indicating the target detecting ability of these micelles. In drug loading and release studies, these micelles had the ability to encapsulate insulin and its release was pH sensitive, being more rapid under intestinal fluid environment, but resisting the drug release at gastric fluid environment. Stability test indicates these micelles had good stability during storage. These results suggest the temperature- and pH-sensitive of the DODA-501 polymeric micelles may be an interesting candidate for oral drug delivery system.

CONTENTS
ABSTRACT (in English)………………………………………………...Ⅰ
ABSTRACT (in Chinese)……………………………….………………..Ⅱ
LIST OF FIGURES AND TABLES…………………………..…………1
Chapter 1 緒論…………………………………………………....3
1.1 研究背景…………………………………………………….………3
1.2 藥物釋放之演進…………………………………………………3
1.3 研究方向…………………………………………………………4
1.4 研究動機…………………………………………………………4
1.5 研究目的…………………………………………………………4
1.6 研究內容…………………………………………………………5
Chapter 2 文獻回顧……….....……...………………………...………..7
2.1 藥物控制釋放…………………………………...…………………..7
2.2 胰島素……………………………………………...………………..7
2.2.1 胰島素之功效……………………………………………………...7
2.2.2 胰島素之特性……………………………………………………...8
2.3 藥物釋放載體…………………………….…………………………8
2.3.1 水膠…………………………………………………………….…...8
2.3.2 微膠體(micelle)簡介………………………………………………8
2.3.3 智慧型微膠體……………………………………………………....9
2.4 微膠體釋放機制……………………………………….…………..10
2.5 智慧型微膠體於藥物傳導系統上之優點…………………….…..10
2.6 異丙基丙烯醯胺(N-isopropylacrylamide, NIPAAm)之特性與應
用……………..…………………………………………………….10
2.7 丙烯酸(Acrylic acid, AAc)之特性與應用……………….……….11
2.8 Dioctadecylamie-501 (DODA-501)之特性與應用……...…….....12
Chapter 3 Introduction………………………..……………………...13
實驗部份之中文概要……………………....………..…………………...15
Chapter 4 EXPERIMENT…………………………………………...17
4.1 Chemicals………………………………………...………….…….17
4.2 Preparation of Dioctadecylamine-501…………...………………17
4.3 Synthesis of DODA- 501-p ( NIPAAm-co-AAc) polymeric
micelles…………………………………………………………….17
4.4 Synthesis of FITC-labeled DODA-501-p(NIPAAm-co-AAc)
polymeric Micelles…………………………………….……….….18
4.5 Synthesis of DODA-501-p(NIPAAm-PEG) polymeric
Micelles………………………………………………………….....18
4.6 Polymer characterization……………………………...…………19
4.7 Morphological and dimensional analysis………………………..19
4.8 Investigation of temperature sensitivity……………..……..……19
4.9 Investigation of pH- sensitivity………...………………………...19
4.10 Confocal laser scanning microscopy (CLSM) Analysis………...20
4.11 Loading of insulin………………..………………………………..20
4.12 Insulin release studies…………………...…………………..……21
4.13 Stability studies of the formulations...…………………..……….21
結果與討論之中文概要……….……………..…………………….…….22
Chapter 5 RESULTS AND DISCUSSION……...……….....……….24
5.1 Polymeric micelle characterization…………...……………...….24
5.2 Morphological and dimensional analysis…………………...…...27
5.3 Thermo- and pH-responsive structural changes of DODA-501-p
(NIPAAm-co-AAc) polymeric micelles…..….. ……………….....29
5.4 Confocal laser scanning microscopy (CLSM) analysis………....32
5.5 Insulin release studies…………………...………………………..34
5.6 Stability studies of the micelles………...………………………...36
Chapter 6 結論………………………………………………………...39
Chapter 6 CONCLUSION…………….……………………………...40
REFERENCES………………………………………………………...41

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