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研究生:張凱琳
研究生(外文):Kai-Ling Chang
論文名稱:親水基團修飾之聚己內酯高分子的粒子劑型研究
論文名稱(外文):Study of particle formulation prepared from hydrophilic group modified poly(ε-caprolactone)
指導教授:林文貞
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:129
中文關鍵詞:半乳糖甲氧基聚乙二醇聚己內酯
外文關鍵詞:poly(ε-caprolactone)methoxy poly(ethylene glycol)galactose
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近二十年來,具備生物可相容性與生物可分解性的生物醫學材料在醫學工程和藥物遞送領域上的應用逐漸受到重視。直鏈式的聚酯類高分子尤其是眾多生物醫學材料中被廣泛應用的一類。聚己內酯具有高結晶性和高親脂性,降解所需耗費時間過久,因此在本實驗中試著引入親水性基團以解決聚己內酯作為藥物載遞系統的限制。
在不使用任何催化劑和溶媒的狀態下,以甲氧基聚乙二醇 (methoxy poly(ethylene glycol))使己內酯單體開環共聚合成聚己內酯-甲氧基聚乙二醇雙嵌段共聚合物,使用核磁共振儀與膠體滲透層析系統確認共聚合物的結構及分子量。合成的雙嵌段共聚合物利用透析法包覆親脂性模式藥物 美洒辛,所得的微膠粒在藥物包覆率上可達86.61±8.21%以上。粒徑以穿透式電子顯微鏡確認,都可在82.17±32.17 nm以下。在動物實驗中,微膠粒以皮下注射的方式投予入大白鼠體內,觀察血漿中藥物濃度曲線與各器官藥物累積量。可以發現微膠粒劑型能達到緩釋效果,增加藥物在血液中停留時間,且能有效率增加藥物在肝、腎、肺的累積量。另外,在體外雙嵌段共聚合物的降解實驗中,可以發現材料在大白鼠的血漿內會有重量上的減少,核磁共振儀顯示出聚乙二醇波峰強度相對性地減少,膠體滲透層析圖譜則顯示出分子量分佈變大,另,示差掃描熱分析儀也顯示整體共聚合物的熔點有上升的現象,種種跡象指出,在大白鼠的血漿中,雙嵌段共聚合物的甲氧基聚乙二醇區段會一定程度地由共聚合物中降解斷鏈。
在另一合成實驗中,半乳糖先以苯乙醚基將一位碳以外的氫氧基全數保護後,在催化劑stannous octoate的協助下,使己內酯單體開環聚合而形成接上半乳糖基的聚己內酯,合成的高分子以核磁共振儀、膠體滲透層析系統、示差掃描熱分析儀與菎酮硫酸法確認分子結構、分子量、分子熔點、玻璃轉移溫度、融化熱與半乳糖基的濃度。菎酮硫酸法所測得的半乳糖基量為0.695 mg/g。將接上半乳糖基的聚己內酯製備成微奈米粒,其包覆親脂性模式藥物 美洒辛的包覆率可達76.86±7.78% ,在倒立式立體顯微鏡下所觀測到的粒徑為3.51±3.36 μm,介在次微米至微米的粒徑大小之間。將微奈米粒劑型皮下投予至大白鼠體內雖然也有緩釋效果,但除了在腎臟的累積量較藥物溶液低之外,在其他器官並沒有顯著的差別。
Biomaterials have been explored in recent years, especially aliphatic polyesters. Poly(��-caprolactone) (PCL) exhibits certain desirable characteristics for drug delivery applications. However, high crystallinity and hydrophobicity result in its long degradation time. Therefore, hydrophilic groups are introduced into the PCL structure in this study to solve theses problems and make PCL more effective as a drug delivery carrier.
Amphiphilic diblock copolymer composing methoxy poly(ethylene glycol) (MEPEG) and PCL was synthesized via a ring-opening polymerization without a catalyst. The molecular structure and average molecular weight were determined by 1H-NMR and GPC. A dialysis method was used to prepare the polymeric micelles containing indomethacin as a hydrophobic model drug. The drug loading efficiency was up to 86.61±8.21%. The particle size of micelles measured by transmission electron microscope was 82.17±32.17 nm. After subcutaneous administering micelles, the plasma concentration profile showed the sustained release of drug from micelles. The AUCs of drug in liver, kidney, and lung after administration of micelles were significantly higher than drug solution. The degradation behavior of diblock copolymer was studied in rat plasma at 37℃. It was found that the weight of the copolymer was lost with time, and the decrease of MEPEG peak intensity was shown in NMR spectrum. The chromatography of GPC also showed the increase of polydispersity during the degradation process. The melting points of degradation products measured by DSC increased with time. These results indicated that the hydrophilic block of the copolymer could be the degradation position to cause this outcome.
Modification of PCL with galactose was another approach to improve the specificity of drug delivery. We used the benzyl ether to protect the hydroxyl group of galactose. The anomeric hydroxyl group in the presence of stannous octoate was used to attack the acyl carbon of ��-caprolactone to evoke the coordination-insertion reaction. The characteristics of the polymer conjugated galactose were identified by 1H-NMR, GPC, and DSC. Each gram of product contained 0.695 mg galactose. The micro-nanoparticles prepared by PCL conjugated galactose were loaded with indomethacin and the drug loading efficiency was up to 76.86±7.78%. The particle size of micro-nanoparticles measured by inverted microscopy was 3.51±3.36 �慆. Although the plasma concentration profile displayed the sustained drug release after subcutaneous administration of micro-nanoparticles, the drug accumulation in organs except kidney was not significantly different from dru
目錄

第一章 緒論 1
一、 生物醫學材料 1
二、 聚己內酯物理化學性質 7
三、 微膠粒遞送系統 9
四、 標的式藥物遞送系統 16
五、 去唾液酸胎醣蛋白接受器 18
六、 碳水化合物的物理化學性質 21
七、 奈米粒特性與製備法 25
第二章 試劑與材料介紹 26
一、 己內酯 26
二、 甲氧基聚乙二醇 26
三、 有辛酸亞錫 27
四、 半乳糖 29
五、 鈀碳催化劑 30
六、 強酸強鹼離子交換樹脂 30
七、 菎酮 (anthrone) 32
八、 美洒辛(indomethacin) 33
第三章 實驗動機與目的 36
第四章 實驗試劑與儀器 37
一、 試劑 37
二、 儀器 39
三、 藥品溶液及緩衝液之配製 43
第五章 實驗方法 45
一、 雙性共聚合物-甲氧基聚乙二醇-聚己內酯的合成 45
二、 聚己內酯-半乳糖高分子聚合物的合成 46
(1) 半乳糖一位碳的甲基化 46
(2) 甲基半乳糖氫氧基的苯乙醚基化 48
(3) 苯乙醚基保護之甲基半乳糖之去甲基 49
(4) 運用苯乙醚基保護之半乳糖氫氧基進行己內酯單體開環反應 50
(5) 氫化反應去苯乙醚基 51
三、 聚己內酯-半乳糖的糖類測定 52
四、 製備微膠粒劑型 53
五、 微奈米粒製備方法 54
六、 美洒辛定量方法 55
(1) 同日內精密度、準確度試驗 55
(2) 異日內精密度、準確度試驗 55
七、 含藥微膠粒與微奈米粒的物性 56
(1) 藥品包覆率 56
(2) 粒徑分析 56
八、 劑型於大白鼠的藥物動力學與體內分佈試驗 56
(1) 血漿中 美洒辛的定量方法 56
(2) 組織內 美洒辛的定量方法 60
(3) 大白鼠給藥及藥物分析 62
九、 雙嵌段共聚合物體外降解試驗 64
(1) 重量殘餘率試驗 64
(2) 分子量評估-膠體滲透層析 65
(3) 質子核磁共振儀分析 67
(4) 示差掃描熱分析儀分析 68
第六章 結果與討論 69
一、 雙性共聚合物—甲氧基聚乙二醇—聚己內酯雙嵌段高分子的合成 69
(1) 產率 70
(2) 質子核磁共振圖譜 70
(3) 膠體滲透層析 72
二、 美洒辛定量精確度試驗 73
三、 微膠粒物性 75
四、 微膠粒劑型於大白鼠的藥物動力學與體內分佈試驗 78
(1) 血漿中 美洒辛分析方法確效 78
(2) 血漿中 美洒辛之絕對回收率 80
(3) 吲哚美洒辛定量方法同日間異日間精密度、準確度試驗 80
(4) 各器官藥物回收率 82
(5) 微膠粒皮下注射入大白鼠體內的藥物動力學研究 83
五、 雙嵌段共聚合物體外(in vitro)降解實驗 89
(1) 重量殘餘率試驗 89
(2) 分子量評估-膠體滲透層析 92
(3) 質子核磁共振儀分析 95
(4) 示差掃描熱分析儀 96
六、 聚己內酯—半乳糖高分子聚合物的合成 97
(1) 半乳糖一位碳的甲基化 97
(2) 甲基半乳糖氫氧基的苯乙醚基化 101
(3) 苯乙醚基保護之甲基半乳糖之去甲基 104
(4) 運用苯乙醚基保護之半乳糖氫氧基進行己內酯單體開環反應 107
(5) 氫化反應去苯乙醚基 108
七、 聚己內酯-半乳糖的糖類測定 112
八、 微奈米粒物性 115
九、 微奈米粒劑型於大白鼠的藥物動力學體內分佈實驗 116
(1) 藥物溶液與微奈米粒在血漿中的藥物動力學研究 116
(2) 藥物溶液與微奈米粒在器官中的藥物動力學研究 117
第七章 結論 120
第八章 參考文獻 122
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