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研究生:李玟娟
研究生(外文):Wen-Chuan Lee
論文名稱:聚酸酐高分子之合成、降解及藥物釋放
論文名稱(外文):Preparation, Degradation Behavior, and Drug Release of Polyanhydrides
指導教授:朱一民朱一民引用關係
指導教授(外文):I-Ming Chu
學位類別:博士
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:2007
畢業學年度:95
語文別:中文
論文頁數:94
中文關鍵詞:聚酸酐生物可降解性藥物控制釋放奈米顆粒
外文關鍵詞:polyanhydridesbiodegradabilitydrug controlled releasenanoparticles
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在過去的研究當中,由於聚酸酐具有高度的生物分解性以及生物相容性,常應用在開發藥物釋放系統。聚酸酐的降解過程為表面侵蝕行為,而這樣的降解方式正適用於藥物釋放系統。隨著奈米技術的開發,越來越多的奈米藥物載體被應用在藥物釋放上面。然而,在這樣微小的尺度,藥物載體的比表面積急遽增加,聚酸酐的降解行為將產生改變,進而牽動藥物釋放行為。因此,本研究利用1,3-雙(對羧基苯氧基)丙烷(1,3-bis(p-carboxyphenoxy)propane, CPP)及癸二酸(sebacic acid, SA)兩類的雙酸單體,利用熔融縮合法進行聚合,形成癸二酸之單聚物(homopolymer)以及共合成之共聚物(copolymer)。利用溶劑置換法(solvent displacement)以及乳化法(emulsification)將聚合物製備形成奈米顆粒,進行降解以及包覆藥物釋放等實驗。此外,錠狀的聚合物亦進行了相同的降解實驗,以進行比較。
由研究結果得知,聚酸酐聚合物可透過此兩種方式,改變聚合物濃度、介面活性劑種類等變因製備出粒徑約在200 nm上下的奈米顆粒。這些奈米顆粒相較於錠狀結構有著快速的降解行為,以癸二酸單聚物而言,錠狀降解時間需時約兩星期,而奈米顆粒的降解時間則在一星期上下,除了比表面積的差異之外,微小化程序以及製備奈米顆粒的方法使得癸二酸的鏈段的結晶度下降亦扮演著相當重要的角色,而加入更具疏水特性的1,3-雙(對羧基苯氧基)丙烷共聚物並非使材料防止水的滲透而不易降解,反而亦抑制了癸二酸的鏈段的結晶,使奈米顆粒的降解時間縮短至兩天。
在包覆藥物方面,喜樹鹼(camptothecin)及紫杉醇(paclitaxel)為測試的疏水性藥物。藥物初始的劑量直接影響了藥物負載的效率,藥物包覆量與顆粒大小呈現正相關,顯示藥物佔據了載體本身的體積。紫杉醇的包覆效率可達藥物載體的10%以上,顯示紫杉醇可順利包覆於聚酸酐材料中。根據包覆喜樹鹼的實驗,奈米顆粒的製備的方式對於藥物的包覆量及釋放行為影響不大,但對於藥物載體降解的行為則有明顯的差異,溶劑置換法所製備出來的奈米顆粒呈現快速的降解而乳化法的降解行為則較為緩慢。此外,不管是何種製備奈米顆粒方式,藥物釋放的行為與藥物載體的降解情形有顯著的不一致性,藥物的釋放速度均較藥物載體降解速度快,藥物於2-3日內則釋放完畢,而載體則為3-4日甚至更久。除了藥物載體製備方式、製備過程中的溶劑揮發可能造成藥物漏失,藥物本身對於材料結晶行為的影響,亦是影響藥物釋放及載體降解行為的重要因素。
Polyanhydrides have been used in many drug delivery systems due to their biodegradability and biocompatibility. Their degradation pattern of surface erosion made them suitable for stable drug release applications. However, in nanoparticle systems, this degradation pattern may not hold, and the drug release kinetics will be different also. In this study, 1,3-bis(p-carboxyphenoxy)propane (CPP) and sebacic acid (SA) were synthesized through melt-condensation into homopolymers and copolymers to investigate the different degradation patterns and drug release mechanisms of disk and nanoparticle.
By solvent displacement and emulsification methods, the polymers were prepared into the nanoparticles with dimension in 200 nm through changing polymer concentrations, and verifying surfactants. PSA disks degraded for about two weeks wile nanoparticles displayed a fast degradation in about one week, depending on the preparation method. Besides the large differences of surface area to volume ratio between disks and nanoparticles, the micronization of the samples and nanoparticles preparation methods inducing decrease of the crystallinity of SA segments of these nanoparticles were important factors of tailoring degradation rates. The copolymers contained with hydrophobic segment of CPP did not preventing water penetrating into the samples to hinder hydrolysis but hindered the crystallization of SA segments, which resulting fast degradation of these nanoparticles.
Camptothecin and paclitaxel, the highly hydrophobic anticancer drugs, were used as modeling drugs. The initial drug loading directly affected the drug loading efficiencies, and also the size of the nanoparticles. The results revealed that drugs themselves occupied the space in the nanoparticles. The drug loading efficiencies of the paclitaxel were over 10% based on polymer weight, which indicating polyanhydrides suitable for encapsulating paclitaxel. In the exams of encapsulation with camptothecin, the drug loading efficiencies and drug release mechanism were independent on the preparation methods. However, the preparation methods dominated the degradation of nanoparticles. The drug release of the nanoparticles all demonstrated an initial burst. In the meantime, the degradation of nanoparticles and drug release displayed significantly inconsistent, i.e. the drug release rates were faster then the nanoparticles degradation rates, the drug released in 2-3 days while degradation lasted for 3-4 days even longer. Besides the preparation methods of nanoparticles, the solvent evaporation procedure, the drug affecting polymer crystallization were also important factors on drug release and nanoparticle degradation.
1. Introduction 1
1.1 Biomaterials 2
1.2 Biodegradable polymers 3
1.3 Polyanhydrides 5
1.3.1 A brief history 7
1.3.2 Synthesis methods 8
1.3.3 Degradation 9
1.3.4 The biocompatibility 10
1.3.5 The applications 12
1.4 Drug controlled release systems 13
1.5 Nanoparticles 15
1.6 Objectives 16

2. Preparation, Characterization and Biodegradation of Polyanhydrides 17
2.1 Backgrounds 18
2.2 Experimental Parts 19
2.2.1 Materials 19
2.2.2 Methods 19
2.2.2.1 Synthesis of 1,3-bis(p-carboxyphenoxy) propane (CPP) 19
2.2.2.2 Polymer synthesis 21
2.2.2.3 Characterization of polymers 22
2.2.2.4 Degradation of polyanhydrides 22
2.3 Results and Discussions 24
2.3.1 The synthesis and characterization of the polymers 24
2.3.2 The degradation of polyanhydrides 28
2.4 Conclusions 31

3. Preparation of Polyanhydrides Nanoparticles as Hydrophobic Drug Carrier by Solvent Displacement Process 33
3.1 Backgrounds 34
3.2 Experimental Parts 37
3.2.1 Materials 37
3.2.2 Methods 37
3.2.2.1 Preparation of nanoparticles 37
3.2.2.2 Hydrophobic drug encapsulated in nanoparticles 37
3.2.2.3 Characterization of nanoparticles 37
3.2.2.4 Drug loading and encapsulation efficiency 38
3.2.2.5 Degradation and drug release study 39
3.3 Results and Discussions 39
3.3.1 Nanoparticle properties 39
3.3.2 Degradation of nanoparticles 43
3.3.3 Drug loading and encapsulation efficiency 45
3.3.4 In vitro release 46
3.4 Conclusions 47

4. Preparation of Polyanhydrides Nanoparticles as Hydrophobic Drug Carrier by Emulsification Evaporation Process 49
4.1 Backgrounds 50
4.2 Experimental Parts 51
4.2.1 Materials 51
4.2.2 Methods 52
4.2.2.1 Preparation of Nanoparticles 52
4.2.2.2 Hydrophobic drugs encapsulated in nanoparticles 53
4.2.2.3 Particles characterization 53
4.2.2.4 Recovery rate, drug loading and encapsulation efficiency 53
4.2.2.5 In vitro study 55
4.3 Results and Discussions 55
4.3.1 Nanoparticle properties 55
4.3.2 Degradation of nanoparticles 61
4.3.3 The encapsulation of camptothecin 63
4.3.4 In vitro study of releasing camptothecin 65
4.3.5 The encapsulation of paclitaxel 68
4.3.6 In vitro study of releasing paclitaxel 69
4.4 Conclusions 72

5. Summary 74

Appendixes 81

References 85
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