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系統識別號 U0002-2007200518065300
中文論文名稱 生物可分解PHA材料包覆四環素藥物之釋放研究
英文論文名稱 Studies on tetracycline drug release behavior of biodegradable poly(hydroxyalkanoate) material
校院名稱 淡江大學
系所名稱(中) 化學工程與材料工程學系碩士班
系所名稱(英) Department of Chemical and Materials Engineering
學年度 93
學期 2
出版年 94
研究生中文姓名 劉淑媛
研究生英文姓名 Shu-Yuan Liu
學號 692360083
學位類別 碩士
語文別 中文
口試日期 2005-06-30
論文頁數 208頁
口試委員 指導教授-董崇民
委員-邱文英
委員-鄭國忠
委員-鄭廖平
委員-孫一明
中文關鍵字 聚羥基丁酯  聚羥基丁酯-羥基戊酯  四環素  藥物釋放 
英文關鍵字 poly(hydroxybutyrate)  poly(hydroxybutyrate-co-hydroxyvalerate)  tetracycline  drug release 
學科別分類
中文摘要 以擠壓米糠/澱粉(1:8)作為碳源,從嗜鹽菌發酵生產出來的聚羥基烷酯經過FTIR及NMR分析後,確認為聚(羥基丁酯-羥基戊酯)共聚合體(Poly(3-hydroxybutyrate-co-3-hydroxyvalerate),PHBV),其中羥基戊酯(HV)單元佔了9.2%。利用刮膜的方式將嗜鹽菌生產的PHBV共聚合體(HmPHBV)及從化學藥品公司提供之聚羥基丁酯單聚合體(PHB)及聚(羥基丁酯-羥基戊酯)共聚合體(HV單元佔8%,PHBV8)製作不同四環素含藥量的薄膜,然後在磷酸鹽緩衝溶液(PBS)中進行藥物釋放實驗。藉由ATR-FTIR、EDS及SEM來觀察四環素在薄膜的分佈情形,結果發現薄膜上表面及截面具有比下表面多的四環素。TGA分析中包覆四環素的PHB及PHBV8薄膜的起始裂解溫度(Tonset)比純PHB及PHBV8的Tonset增加了約20oC,而嗜鹽菌生產的HmPHBV則約提高了10oC。包覆四環素藥物的PHB、PHBV8及HmPHBV薄膜在磷酸鹽緩衝溶液(PBS)進行釋放,所有的薄膜在20小時之內達到最大藥物累積釋放量。在藥物釋放部分中,包覆四環素的PHB、PHBV8及HmPHBV薄膜皆呈現二階段釋放模式。另外利用單乳化製作包覆四環素的PHB微粒,水相中分別使用了界面活性劑Tween80及水溶性高分子(WCS),其作用皆為幫助油相(氯仿)形成分散的油滴。使用Tween80製造PHB微粒的優點為微粒中四環素的包覆率及裝載量皆比使用WCS所製造的PHB微粒高,而使用WCS所製造的PHB微粒的優點為微粒的產率較高,若混合使用Tween80及WCS製造PHB微粒的四環素包覆率及裝載量與單獨使用WCS一樣低。原因在於四環素雖然溶於氯仿,卻大部分會擴散至水中,因此在單乳化的實驗中,PHB微粒包覆四環素的產率、包覆率及裝載量皆很低。
英文摘要 In this study, poly(hydroxyalkanoate) was produced by Haloferax Mediterranei. The poly(hydroxyalkanoate) was analyized by FTIR and NMR. Poly(hydroxybutyrate-co-hydroxyvalerate), PHBV (HmPHBV), confirmed the structure of the poly(hydroxyalkanoate). The HV content of the HmPHBV was only 9.2 mol%. Poly(hydroxybutyrate), PHB, and poly(hydroxybutyrate-co-hydroxyvalerate), PHBV (PHBV8), were provided by Aldrich, and the HV content of PHBV8 was 8 mol%. PHB, PHBV8 and HmPHBV membranes which were contained tetracycline were made by scraping method. The distributions of tetracycline in the membranes were investigated by FTIR, SEM and EDS. Tetracycline existed on the top and in the cross-section of the membranes was more then it existed on the bottom of the membranes. In the TGA analysis, the maxium degradation temperature of PHB and PHBV8 membranes containg tetracycline were increased 20oC then pure membranes. And the temperature of HmPHBV containg tetracycline membranes was increased about 10oC then pure HmPHBV membrane. The drug release experiment was monitored in a buffer solution (PBS) at 37oC. Abount 20 hours, drug release amounts of all membranes were almost the largest. Releasing models of PHB and PHBV8 membranes were first-order release model, and HmPHBV membranes was t1/2 release model.Single emulsion (O/W) was used to made PHB microparticles containing tetracycline. Surfactant (Tween80) and carboxymethyl chitosan (WCS) were prevented from oil drops aggregating in water phase. Structures of PHB microparticles were observed using SEM. The adventage of using Tween80 as emulsifier was that the encapsulation efficiency and loading of PHB microparticles were higher then that of the PHB micropartilces being made by using WCS as emulsifier. But the yield of PHB microparticles using WCS as emulsifier was higher that using Tween80. If Tween80 and WCS were togegher using as emulsifier, problems of the lower encapsulation efficiency and loading of PHB microparticles still could not be solved.
論文目次 目 錄

中文摘要 I
Abstract III
目 錄 V
圖 目 錄 IX
表 目 錄 XVI
符號表 XX
第一章 緒論 1
1-1生物可分解聚酯的應用 1
1-2藥物控制釋放技術 3
1-3研究目的 4
第二章 文獻回顧 6
2-1 PHA的結構 6
2-2 PHA的發展歷史 8
2-3 PHB及PHBV的生化合成過程 9
2-4 PHB及PHBV的發酵生產 9
2-5 PHB及PHBV從微生物分離的程序 12
2-6 PHB及PHBV的性質 13
2-7 PHA在藥物釋放的應用 15
2-8四環素介紹 17
2-9四環素在藥物釋放的應用 19
2-10 PHB及PHBV與四環素類相關文獻 28
2-11水溶性幾丁聚醣 30
2-12界面活面劑與乳化作用 32
2-12-1界面活性劑的定義 32
2-12-2非離子性界面活性劑 33
2-12-3 HLB值與界面活性劑的關係 36
2-12-4乳化的原理 36
2-12-5單乳化(油/水(O/W)) 38
2-12-6雙乳化(水/油/水(W1/O/W2)) 39
2-12-7微胞的形成 39
2-13藥物釋放類型及釋放動力原理 42
2-13-1藥物釋放之類型 42
2-13-2 Fick’s First Law觀念 45
2-13-3零階、一階及t-1/2的藥物釋放模型 46
2-13-4時間延遲(time lag)與突釋現象(burst effect) 49
2-13-5藥物釋放之動力原理 50
第三章 實驗 60
3-1實驗藥品 60
3-2實驗儀器 61
3-3實驗步驟 63
3-3-1檢量線的製作 63
3-3-2包覆四環素之PHB及PHBV薄膜製作 64
3-3-3包覆四環素的PHB及PHBV薄膜之藥物釋放 66
3-3-4單乳化(O/W)溶劑揮發法製作包覆四環素之PHB及PHBV微粒 67
3-4紫外光光譜分析(UV) 71
3-5傅利葉紅外線光譜儀分析(FTIR-ATR) 71
3-6場發射掃描式電子顯微鏡分析(SEM) 71
3-7 X光繞射分析儀分析(XRD) 71
3-8核磁共振光譜儀分析(NMR) 71
3-9微分掃描卡計分析(DSC) 72
3-10膠體滲透層析儀分析(GPC) 72
3-11熱重分析儀分析(TGA) 72
第四章 結果與討論 73
4-1嗜鹽菌生產的PHA結構鑑定 73
4-2熱轉移性質 77
4-3水溶性幾丁聚醣的結構鑑定 79
4-4檢量線的製作 80
4-5 PHB及PHBV包覆四環素薄膜的結構與性質測定 90
4-5-1 ATR-FTIR分析 90
4-5-2 結晶構造分析 96
4-5-3熱裂解行為 101
4-5-5薄膜形態 107
4-5-6 EDS分析 142
4-5-7系統一、二、三、四薄膜在釋放後內部藥物殘餘量的測量 144
4-6系統一、二、三、四薄膜的藥物釋放動力 146
4-7單乳化(油/水(O/W))方法製備PHB包覆四環素藥物微粒 164
4-7-1 PHB微粒的製程探討 164
4-7-2 PHB包覆四環素藥物微粒的SEM分析 170
第五章 結論 178
第六章 參考文獻 180
附錄 189


圖 目 錄
圖1-1藥物釋放的理論濃度範圍 3
圖2-1 PHA的結構 6
圖2-2 PHB的結構 7
圖2-3 PHBV的結構 7
圖2-4微生物生化合成PHB及酵素解聚合的過程【3】 10
圖2-5四環素(tetracycline base)的分子結構 18
圖2-6鹽酸四環素(tetracycline hydrochloride)的分子結構 18
圖2-7聚合物接枝與藥物鍵結的示意圖【43】 22
圖2-8水溶性幾丁聚醣的結構 31
圖2-9界面活性劑的分類 33
圖2-10 D-葡萄糖轉變成D-山梨糖醇的氫化反應 34
圖2-11 Span系列的結構 34
圖2-12 Tween系列的結構 35
圖2-13界面活性劑在水油界面的排列 38
圖2-14乳液中顆粒分散的型態 38
圖2-15表面張力-濃度曲線與界面活性劑之溶解狀態 40
圖 2-16微胞的形狀【77】 40
圖2-17 Critical packing parameters(CPP=V/al) of surfactant molecules and preferred aggregate structures for geometrical packing reasons(V:圓錐部分的體積、l:圓錐最大長度、a:圓錐最大半徑)【77】 41
圖2-18儲槽式(reservoir device)藥物釋放模式 42
圖2-19整體式(monolithic device)藥物釋放模型 43
圖2-20溶蝕式(erosion type)藥物釋放模型 43
圖2-21化學反應式(chemical reactions type)釋放模型 44
圖2-22膨潤式(swelling type)藥物釋放模型 44
圖2-23滲透式(osmosis type)藥物釋放模型 45
圖2-24零階、一階及t-1/2的藥物累積釋放量與時間關係圖 47
圖2-25零階、一階及t-1/2的藥物釋放速率與時間關係圖 47
圖2-26時間延遲及突釋現象的藥物累積釋放量與時間的關係 49
圖2-27儲槽式濃度梯度圖(a)Steady-state concentration模式 51
(b)Unsteady-state(pseudo-steady-state)模式 51
圖2-28整體式濃度梯度圖(a)dissolved形態(b)dispersed形態 54
圖4-1市售PHB及PHBV8與HmPHBV的ATR-FTIR圖 74
圖4-2嗜鹽菌生產的HmPHBV的1H-NMR圖 75
圖4-3嗜鹽菌生產的HmPHBV的13C-NMR圖 75
圖4-4 PHBV結構圖位置標示 76
圖4-5 純PHB的熱示差掃描圖 78
圖4-6純PHBV8的熱示差掃描圖 78
圖4-7純HmPHBV的熱示差掃描圖 79
圖4-8水溶性幾丁聚醣的ATR-FTIR圖 80
圖4-9四環素在磷酸鹽緩衝溶液(PBS)中不同時間(照光)的UV圖 81
圖4-10四環素在磷酸鹽緩衝溶液(PBS)中不同時間(不照光)的UV圖 82
圖4-11四環素在磷酸鹽緩衝溶液(PBS)中不同標準溶液的UV圖 83
圖4-12四環素在磷酸鹽緩衝溶液(PBS)中的檢量線圖 83
圖4-13四環素在水中不同標準溶液的UV圖 85
圖4-14四環素在水中的檢量線圖 85
圖4-15四環素在溶有PHB的氯仿中的UV圖 86
圖4-16四環素在溶有PHB的氯仿中的檢量線圖 87
圖4-17不同比例標準溶液求水/氯仿的分散係數K值 88
圖4-18 Tween80在水中的UV圖 89
圖4-19純四環素(粉末)ATR-FTIR圖 91
圖4-20系統一的PHB(含藥物)薄膜上表面ATR-FTIR分析 92
圖4-21系統一的PHB(含藥物)薄膜下表面ATR-FTIR分析 92
圖4-22系統二的PHB(含藥物)薄膜上表面ATR-FTIR分析 93
圖4-23系統二的PHB(含藥物)薄膜下表面ATR-FTIR分析 93
圖4-24系統三的PHBV8(含藥物)薄膜上表面ATR-FTIR分析 94
圖4-25系統三的PHBV8(含藥物)薄膜下表面ATR-FTIR分析 94
圖4-26系統四的HmPHBV(含藥物)薄膜上表面ATR-FTIR分析 95
圖4-27系統四的HmPHBV(含藥物)薄膜下表面ATR-FTIR分析 95
圖4-28系統一的PHB(含藥物)薄膜上表面的XRD圖 97
圖4-29系統一的PHB(含藥物)薄膜下表面的XRD圖 97
圖4-30系統二的PHB(含藥物)薄膜上表面的XRD圖 98
圖4-31系統二的PHB(含藥物)薄膜下表面的XRD圖 98
圖4-32系統三的PHBV8(含藥物)薄膜上表面的XRD圖 99
圖4-33系統三的PHBV8(含藥物)薄膜下表面的XRD圖 99
圖4-34系統四的HmPHBV(含藥物)薄膜上表面的XRD圖 100
圖4-35系統四的HmPHBV(含藥物)薄膜下表面的XRD圖 100
圖4-36系統一的PHB(含藥物)薄膜的熱重量損失圖 102
圖4-37系統二的PHB(含藥物)薄膜的熱重量損失圖 102
圖4-38系統三的PHBV8(含藥物)薄膜的熱重量損失圖 103
圖4-39系統四的HmPHBV (含藥物)薄膜的熱重量損失圖 103
圖4-40系統一的PHB(含藥物)薄膜的微分圖 104
圖4-41系統二的PHB(含藥物)薄膜的微分圖 104
圖4-42系統三的PHBV8(含藥物)薄膜的微分圖 105
圖4-43系統四的HmPHBV(含藥物)薄膜的微分圖 105
圖4-44純四環素粉末 107
圖4-45純PHB、PHBV8及HmPHBV薄膜上表面SEM圖 110
圖4-46純PHB、PHBV8及HmPHBV薄膜下表面SEM圖 111
圖4-47純PHB、PHBV8及HmPHBV薄膜截面SEM圖 112
圖4-48 PHB薄膜(含藥物)在藥物釋放前的上表面圖 113
圖4-49系統一的PHB(含藥物)薄膜在藥物釋放前的上表面圖 114
圖4-50系統二的PHB(含藥物)薄膜在藥物釋放前的上表面圖 115
圖4-51 PHB(含藥物)薄膜在藥物釋放前的下表面圖 117
圖4-52系統一的PHB(含藥物)薄膜在藥物釋放前的下表面圖 118
圖4-53系統二的PHB(含藥物)薄膜在藥物釋放前的下表面圖 119
圖4-54 PHB(含藥物)薄膜在藥物釋放前的截面圖 121
圖4-55系統一的PHB(含藥物)薄膜在藥物釋放前的截面圖 122
圖4-56系統二的PHB(含藥物)薄膜在藥物釋放前的截面圖 123
圖4-57系統一的PHB(含藥物)薄膜在藥物釋放後的上表面圖 124
圖4-58系統二的PHB(含藥物)薄膜在藥物釋放後的上表面圖 125
圖4-59系統一的PHB(含藥物)薄膜在藥物釋放後的下表面圖 126
圖4-60系統二的PHB(含藥物)薄膜在藥物釋放後的下表面圖 127
圖4-61系統一的PHB(含藥物)薄膜在藥物釋放後的截面圖 128
圖4-62系統二的PHB(含藥物)薄膜在藥物釋放後的截面圖 129
圖4-63系統三的PHBV8(含藥物)薄膜在藥物釋放前的上表面圖 130
圖4-64系統三的PHBV8(含藥物)薄膜在藥物釋放前的下表面圖 131
圖4-65系統三的PHBV8(含藥物)薄膜在藥物釋放前的截面圖 132
圖4-66系統三的PHBV8(含藥物)薄膜在藥物釋放後的上表面圖 133
圖4-67系統三的PHBV8(含藥物)薄膜在藥物釋放後的下表面圖 134
圖4-68系統三的PHBV8(含藥物)薄膜在藥物釋放後的截面圖 135
圖4-69系統四的HmPHBV(含藥物)薄膜在藥物釋放前的上表面圖 136
圖4-70系統四的HmPHBV(含藥物)薄膜在藥物釋放前的下表面圖 137
圖4-71系統四的HmPHBV(含藥物)薄膜在藥物釋放前的截面圖 138
圖4-72系統四的HmPHBV(含藥物)薄膜在藥物釋放後的上表面圖 139
圖4-73系統四的HmPHBV(含藥物)薄膜在藥物釋放後的下表面圖 140
圖4-74系統四的HmPHBV(含藥物)薄膜藥物釋放後的截面圖 141
圖4-75系統一的薄膜在不同時間的藥物累積釋放量 150
圖4-76系統二的薄膜在不同時間的藥物累積釋放量 151
圖4-77系統三的薄膜在不同時間的藥物累積釋放量 152
圖4-78系統四的薄膜在不同時間的藥物累積釋放量(Mt) 153
圖4-79系統一的薄膜在不同時間的藥物累積釋放百分比 154
圖4-80系統二的薄膜在不同時間的藥物累積釋放百分比 155
圖4-81系統三的薄膜在不同時間的藥物累積釋放百分比 156
圖4-82系統四的薄膜在不同時間的藥物累積釋放百分比 157
圖4-83系統一的PHB(含藥物)薄膜的藥物對數式釋放動力模式 160
圖4-84系統二的PHB(含藥物)薄膜的藥物對數式釋放動力模式 161
圖4-85系統三的PHBV8(含藥物)薄膜的藥物對數式釋放動力模式 161
圖4-86系統四的HmPHBV(含藥物)薄膜的藥物對數式釋放動力模式 162
圖4-87不同轉速(10000、14000、18000rpm)對乳化的影響 167
圖4-88不同溶劑揮發溫度(40、50oC)對乳化的影響 168
圖4-89不同Tween80量(0.0234、0.0468、0.1875g)對乳化的影響 169
圖4-90 Tween80系列PHB微粒(Tw005~Tw02)的結構形態 172
圖4-91 WCS系列PHB微粒(CS005~CS02)的結構形態 174
圖4-92 Tween80/WCS作為界面活性劑所獲得的PHB微粒的實驗結果 176
附錄圖-1 Tween80在水中的UV光譜圖 190
附錄圖-2 Tween80在水中的檢量線圖 190
附錄圖-3不同轉速、溶劑揮發溫度及時間所製成的PHB微粒 206

表 目 錄

表2-1各種不同側基的PHA 6
表2-2可生產PHB的微生物 7
表2-3 PHA發展簡述 8
表2-4可溶解PHB的溶劑溶解度參數比較表【27】 14
表2-5 Span系列的R基結構及HLB值 35
表2-6 Tween系列的R基結構及HLB值 35
表2-7界面活性劑的HLB值和水溶性的關係 37
表2-8 HLB值與界面活性劑用途之關係 37
表3-1 系統一的薄膜代號 65
表3-2 系統二的薄膜代號 65
表3-3系統三的薄膜代號 66
表3-4系統四的薄膜代號 66
表3-5 Tween80系列的樣品代號 68
表3-6 WCS系列的樣品代號 69
表3-7 Tween80與WCS系列的樣品代號 70
表4-1 NMR分析結果 76
表4-2 PHB及PHBV的分子量值 77
表4-3四環素在磷酸鹽緩衝溶液(PBS)中的不同標準溶液 82
表4-4四環素溶於水中的不同標準溶液 85
表4-5四環素在含有PHB的氯仿溶液中的標準溶液 86
表4-6不同比例標準溶液求水/氯仿的分散係數K值 88
表4-7系統一的PHB(含藥物)薄膜的起始裂解溫度( Tonset)及600oC時殘餘的焦碳含量(char yield),升溫速率為20oC/min 106
表4-8系統二的PHB(含藥物)薄膜的起始裂解溫度( Tonset)及600oC時殘餘的焦碳含量(char yield),升溫速率為20oC/min 106
表4-9系統三的PHBV8(含藥物)薄膜的起始裂解溫度( Tonset)及600oC時殘餘的焦碳含量(char yield),升溫速率為20oC/min 106
表4-10系統四的HmPHBV(含藥物)薄膜的起始裂解溫度( Tonset)及600oC時殘餘的焦碳含量(char yield),升溫速率為20oC/min 107
表4-11薄膜中的C原子個數比 143
表4-12薄膜中的O原子個數比 143
表4-13薄膜中的N原子個數比 143
表4-14系統一薄膜在釋放後內部藥物殘餘量的測量 144
表4-15系統二薄膜在釋放後內部藥物殘餘量的測量 144
表4-16系統三薄膜在釋放後內部藥物殘餘量的測量 145
表4-17系統四薄膜在釋放後內部藥物殘餘量的測量 145
表4-18系統一、二、三、四不同釋放百分比 149
表4-20系統一的兩段釋放動力模式n及R值 162
表4-21系統二的兩段釋放動力模式n及R值 163
表4-22系統三的兩段釋放動力模式n及R值 163
表4-23系統四的兩段釋放動力模式n及R值 163
表4-24文獻中水相及油相比例的比較表 165
表4-25轉速、溶劑揮發溫度及時間的影響 166
表4-26 Tween80作為界面活性劑所獲得的PHB微粒的實驗結果 173
表4-27 WCS作為界面活性劑所獲得的PHB微粒的實驗結果 175
表4-28 Tween80及WCS系列微球的實驗結果 177
附錄表-1 Tween80在水中的不同標準溶液 189
附錄表-2藥物累積釋放量的計算式 191
附錄表-3系統一實驗紀錄 195
附錄表-4系統二實驗紀錄 195
附錄表-5系統三實驗紀錄 195
附錄表-6系統四實驗紀錄 195
附錄表-7系統一(HB1及HB2)實驗記錄 196
附錄表-8系統一(HB3及HB4)實驗記錄 197
附錄表-9系統二(HB01及HB02)實驗記錄 198
附錄表-10系統二(HB03及HB04)實驗記錄 199
附錄表-11系統三(HV01及HV02)實驗記錄 200
附錄表-12系統三(HV03及HV04)實驗記錄 201
附錄表-13系統四(Hm01及Hm02)實驗記錄 202
附錄表-14系統四(Hm03及Hm04)實驗記錄 203
附錄表-15四環素在水相損失的重量(Tween80系列) 206
附錄表-16微粒中四環素的重量(Tween80系列) 207
附錄表-17四環素在水相損失的重量(WCS系列) 207
附錄表-18微粒中四環素的重量(WCS系列) 207
附錄表-19四環素在水相損失的重量(Tween80及WCS系列) 208
附錄表-20微粒中四環素的重量(Tween80及WCS系列) 208

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