臺灣博碩士論文加值系統

本研究以幾丁聚醣與三聚磷酸鈉(TPP)經由離子凝膠法(ionic gelation process)製備奈米微粒作為降血脂藥物(lovastatin)傳遞載體。以粒徑分析儀量測粒徑及界面電位，經由zeta-potential判斷粒子在溶液中分散的穩定度。並以TEM、FTIR、TGA及MDSC進行物理性質及結構鑑定分析，於37℃時模擬人體腸道(pH7.4)、胃道(pH1.2)做體外釋放，以RP-HPLC分析lovastatin釋放量。所製備微粒之粒徑範圍介於100~1000nm間，影響粒徑大小及藥物包覆率主要因素為幾丁聚醣分子量(Mw)、幾丁聚醣濃度與初始lovastatin的濃度，幾丁聚醣分子量從30kDa增加至400kDa時，藥物(lovastatin)的包覆率明顯地隨之而增加，幾丁聚醣濃度增加時，包覆率降低，粒徑大小與包覆率無明顯關係。從FTIR、MDSC判斷藥物與微粒間僅為物理吸附。TEM顯示幾丁聚醣奈米微粒於不同分子量皆為圓球形狀，且粒徑分佈均勻。Zeta potential顯示改變不同參數之幾丁聚醣奈米微粒懸浮溶液分散性皆良好，包覆lovastatin後zeta電位降低。模擬人體腸道(pH7.4)釋放量方面，分子量從30增至400kDa時，初始累積釋放速率降低；幾丁聚醣濃度增加時，累積釋放速率增加；lovastatin的累積釋放百分比隨著lovastatin濃度增加而減少。模擬腸道中釋藥行為符合零級釋放模式和Higuchi釋放模式。

The aim of this thesis is to evaluate potential of chitosan nanoparticles as carriers for the cholesterol-lowering drug, lovastatin. Lovastatin–chitosan nanoparticles were prepared by ionotropic gelation of chitosan and tripolyphosphate pentasodium(TPP). The physicochemical properties of nanoparticles were determined by zeta potential analysis, transmission electron microscope, FTIR, MDSC and TGA. Release study was conducted by in vitro investigation to simulate intestinal fluid and gastric fluid at 37 oC. The diameter of prepared nanoparticles was controlled in the range of 100~1000nm. Factors included molecular weight, concentration of chitosan, and initial lovastatin concentration, have been examined to investigate effect on particle size and encapsulation of lovastatin. Experimental results showed that lovastatin encapsulation efficiency was enhanced obviously with increasing molecular weight of chitosan from 30 to 400kDa, but, decreasing with chitosan concentration. The particle size is independent of encapsulation efficiency. Spectrograms of FTIR and MDSC showed that lovastatin physically absorbed by chitosan matrix. TEM photographs demonstrated prepared nanoparticles were in spherical shape and narrow diameter distribution. Zeta potential displayed aqueous of chitosan nanoparticles suspension is stable by altering different parameters. Zeta potential of chitosan nanoparticles decreased after lovastatin loaded. The initial release rates in simulated intestinal fluid decreased along with larger molecular weight of chitosan from 30 to 400 kDa, however increased by increasing of initial chitosan concentration. The release profiles were fitted very well by both the zero order model and the Higuchi release model.

中文摘要 .......................................................i
英文摘要 ……………………………………………………………. ii
目錄 ………………………………………………………......... iv
表目錄 ………………………………………………………......... vii
圖目錄 ………………………………………………………......... viii
一、 前言………………………………………………………. 1
二、 文獻回顧……………………………………………......... 2
2.1 藥物控制釋放技術………………………………............. 2
2.1.1 傳統藥劑與控制釋放藥劑釋藥途徑的比較……………. 2
2.1.2 控制釋放微粒釋藥情形………………………................ 3
2.2 藥物控制釋放動力學模式………….........................6
2.2.1 一階溶出模式……………………………………………. 6
2.2.2 Higuchi間質化溶出模式………………………………... 8
2.2.3 零階溶出模式……………………………………………. 9
2.3 微粒包覆技術……………………………………………. 10
2.4 奈米藥物載體.................................. 11
2.4.1 奈米藥物載體的製造方法…………………………......... 13
2.4.2 奈米藥物載體之材料……………………………………. 14
2.5 幾丁質與幾丁聚醣………………………………………. 15
2.5.1 幾丁質……………………………………………………. 15
2.5.2 幾丁聚醣…………………………………………………. 16
2.5.3 幾丁聚醣在生物醫學材料方面的應用…………………. 18
2.5.4 安全性……………………………………………………. 18
2.6 幾丁聚醣奈米微粒載體…………………………………. 19
2.6.1 幾丁聚醣於藥學上的應用………………………………. 19
2.6.2 幾丁聚醣奈米微粒於藥學上的應用……………………. 19
2.7 降膽固醇劑………………………………………………. 22
三、 實驗材料與方法………………………………................ 25
3.1 實驗材料…………………………………….................. 25
3.1.1 傳輸載體…………………………………………............. 25
3.1.2 藥物……………………………………...................... 25
3.1.3 溶劑………………………………...........................25
3.1.4 交聯劑…………………………………...................... 25
3.2 實驗儀器………………...................................25
3.2.1 乾燥儀器………………….................................25
3.2.2 釋放裝置…………………………...........................26
3.2.3 分析儀器………………………………...................... 26
3.3 幾丁聚醣、Lovastatin熱重分析步驟……………………...... 26
3.4 Lovastatin定量分析……………………………………........ 27
3.5 幾丁聚醣奈米顆粒…………………..….................... 27
3.5.1 製備……………………...................................27
3.5.2 幾丁聚醣奈米微粒粒徑大小與界面電位量測…………........ 30
3.5.3 傅利葉轉換紅外線光譜分析……….........................30
3.5.4 調幅式微差掃描熱分析………………….................... 30
3.5.5 穿透電子顯微鏡分析……………….…………………… 30
3.5.6 體外釋放實驗……………………………………….…… 31
四、 結果與討論…………………………………………......... 32
4.1 結構鑑定分析…………………………….................... 32
4.1.1 熱重分析…………………………………………………. 32
4.1.2 Lovastatin定量分析.....................................36
4.1.3 FTIR光譜分析…………………………………………... 36
4.1.4 調幅式微差掃描熱析…………….......................... 42
4.2 不同幾丁聚醣分子量影響………………................. 48
4.2.1 穿透式電子顯微鏡………………………………………. 48
4.2.2 粒徑分佈…………………………………………………. 48
4.2.3 分子量對粒徑大小及zeta potential的影響……............ 55
4.3 粒徑大小分析……………………………………………. 55
4.4 藥物含量分析……………………………………………. 58
4.5 幾丁聚醣濃度與Lovastatin初始濃度於奈米微粒中的粒徑大小對
zeta potential的影響………………………................63
4.6 體外釋放實驗……………………………………………. 63
4.6.1 模擬胃道中(pH1.2 HCl)之體外釋放實驗……………… 63
4.6.2 模擬腸道中(pH7.4 PBS)之體外釋放實驗……………… 69
4.7 模擬腸道(pH7.4 PBS)實驗之藥物釋放動力學探討…… 70
五、 結論………………………………………………………. 96
六、 參考文獻…………………………………………………. 98

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