臺灣博碩士論文加值系統

近年來，以雙性共聚合物形成微膠粒來當作親脂性藥物載體，已經被廣泛的探討。微膠粒厭水性的核心可以提供一個有利於包埋親脂性藥物的環境；而親水性的外冠則可以穩定核心與外相溶媒所形成的界面。
在本研究中，以三種內酯單體 (e-己內酯、d-戊內酯與L-乳酸酯) 和二種不同分子量的聚乙二醇（聚乙二醇4000、聚乙二醇10000）聚合形成的三嵌段共聚合物，利用透析法製備包覆親脂性模式藥物 美洒辛的微膠粒劑型，測定其包覆率與粒徑，並且在37℃，pH 7.2的磷酸緩衝液中進行體外釋離試驗。微膠粒的生體可相容性是以細胞毒性試驗來評估，並進一步以雄性Wistar大白鼠來觀察微膠粒劑型在活體內藥物動力學性質。
實驗所得的微膠粒包覆率高低受共聚合物親脂端性質與結構的影響而有所不同，親脂性高且結構不具支鏈的共聚合物微膠粒，其包覆率較高；而平均粒徑差不多是200 nm。體外釋離曲線證實 美洒辛從微膠粒的釋放具有緩慢釋出的效果。細胞毒性試驗的結果顯示，除了高濃度（10-3 g/mL）的聚戊內脂-聚乙二醇微膠粒可能具有生體不相容性外，聚己內脂組與聚乳酸酯組的細胞存活率均與對照組無顯著差異。在大白鼠藥物動力學研究中發現，皮下注射含藥微膠粒，藥物在體內的排除速率降低，使半衰期增加，顯示以微膠粒包覆藥物具有緩慢釋放的性質；觀察血中濃度經時變化曲線下面積，微膠粒組明顯較大，表示體內吸收總量較 美洒辛藥物溶液大；然而這樣的結果在口服投予和靜脈注射的實驗中並沒有被觀察到。
總結上述，本實驗針對共聚合物微膠粒體外的特性與體內的藥物動力學性質進行探討，這些結果將有助於瞭解如何將雙性共聚合物應用在微膠粒藥物遞送系統上。

Micelles formed from amphiphilic copolymers have been explored in recent years as carriers for hydrophobic drugs. The hydrophobic micelle core serves as a microenvironment for the incorporation of lipophilic drugs, while the corona shell serves as a stabilizing interface between the hydrophobic core and the external medium.
In our studies, three kinds of monomers (e-caprolactone, d-valerolactone and L-lactide) and poly(ethyl glycol)s with different molecular weights (PEG4000 and PEG10000) were used to prepare triblock copolymers. A dialysis method was used to prepare the polymeric micelles containing indomethacin as a hydrophobic model drug. The drug loading and particle sizes of the micelles were determined. In vitro release studies were performed in a pH 7.2 phosphate buffer solution at 37℃, and the cytotoxicity tests were designed to evaluate the biocompatibility of the polymeric micelles. Furthermore, animal studies were conducted in male Wistar rats to observe in vivo pharmacokinetic properties of the micelles.
The drug loading of the micelles was related to the hydrophobicity and structure of copolymers. The polymeric micelles which were more hydrophobic and without branched had higher drug loading. The particle sizes of the micelles were about 200 nm, and the release profiles indicated the release of indomethacin from micelles exhibited a sustained release behavior. The cytotoxicity tests showed that the cell viability after treated with PCL-PEG and PLA-PEG micelles was insignificant, but PVL-PEG micelles might be not biocompatible if treated with cells in high concentration (10-3 g/mL). In animal pharmacokinetic study, it was found that the amounts of absorption increased after subcutaneous administering micelles. The slow elimination behavior indicated the sustained release property of the drug from micelles. However, these results were not observed if the micelles were administered orally or intravenously.
In summary, in vitro characterization and in vivo pharmacokinetic properties of the polymeric micelles were studied. These outcomes may be useful for the development of micelle drug carrier.

緒論 1
一、 生物醫學材料 1
二、 微膠粒遞送系統 4
三、 細胞毒性試驗 10
四、 微膠粒遞送系統藥物動力學及藥物效用學研究 12
第二章 材料與試劑介紹 15
一、 聚己內酯-聚乙二醇-聚己內酯 15
二、 聚戊內酯-聚乙二醇-聚戊內酯 15
三、 聚乳酸酯-聚乙二醇-聚乳酸酯 16
四、 美洒辛(indomethacin) 17
五、 IMR-90細胞株 19
六、 MTT試劑 19
第三章 實驗動機與目的 21
第四章 實驗試劑與儀器 22
一、 試劑 22
二、 儀器 25
三、 藥品溶液及緩衝液之配製 27
第五章 實驗方法 30
一、 製備微膠粒劑型 30
二、 美洒辛定量法 31
(1) 同日內精密度、準確度試驗 32
(2) 異日內精密度、準確度試驗 32
三、 含藥微膠粒的物性 32
(1) 藥品包覆率 32
(2) 粒徑分析 33
四、 體外釋離試驗 34
五、 細胞培養 35
(1) 培養程序及條件 35
(2) 細胞冷凍方法 36
(3) 細胞解凍方法 36
六、 不同共聚合物形成微膠粒之細胞存活率試驗 36
七、 微膠粒劑型於活體 (in vivo) 中藥物動力學試驗 37
(1) 動物埋管手術 37
(2) 藥物動力學實驗 39
(3) 血漿中 美洒辛的定量方法 41
(4) 數據分析及統計方法 42
第六章 結果與討論 45
一、 美洒辛定量精確度試驗 45
二、 藥品包覆率 50
三、 粒徑分析 51
四、 體外釋離試驗 52
(1) 聚己內脂-聚乙二醇微膠粒，其藥品之釋離曲線 52
(2) 聚戊內脂-聚乙二醇微膠粒，其藥品之釋離曲線 53
(3) 聚乳酸脂-聚乙二醇微膠粒，其藥品之釋離曲線 54
(4) 比較微膠粒劑型與 美洒辛藥物溶液釋離曲線 56
五、 雙性共聚合物形成微膠粒之細胞存活率試驗 58
六、 美洒辛在血漿中分析方法確效 62
七、 微膠粒劑型於大白鼠體內藥物動力學試驗 65
(1) 皮下注射部分 66
(2) 口服投予部分 73
(3) 靜脈注射部分 77
第七章 結論 81
第八章 參考文獻 82

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