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研究生:方逸萍
研究生(外文):Yi-Ping Fang
論文名稱:研製具有局部性之5-aminolevulinicacid微脂粒及其對皮膚疾病之光動力療效評估
論文名稱(外文):Investigation of 5-aminolevulinic acid in liposome as localized carrier and application in skin disease for photodynamic therapy
指導教授:蔡義弘蔡義弘引用關係
指導教授(外文):Yi-Huang Tsai
學位類別:博士
校院名稱:高雄醫學大學
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:2008
畢業學年度:97
語文別:中文
論文頁數:121
中文關鍵詞:5-胺基酮戊酸鹽酸鹽微脂粒乙醇微脂粒雷射共軛焦顯微鏡經皮穿透能力皮膚增生光動力療法
外文關鍵詞:5-aminolevulinic acidl iposomeethosomeconfocal laser scanning microsopypenetration abilityhyperproliferative skinphotodynamic therapy
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光動力療法屬於一種非侵犯的技術,對於皮膚疾病為一替代的治療方式。而5-aminolevulinic acid (ALA)此光敏感藥物為一前驅藥物,經由外加投與後產生有效代謝物原紫質環(Protoporphyrin IX;PpIX)。當原紫質環被適當光源激發後,光化學反應會產生摧毀惡性及非惡性組織。然而,ALA此化合物具兩性離子的特性,造成穿透細胞膜或皮膚的限制。本研究利用劑型設計適當載體,包括微脂粒(liposome)及乙醇微脂粒(ethosome),期望對於ALA經皮膚傳遞有所改善。利用物化性質篩選適當的載體,涵蓋處方的粒徑測定、界面電位、藥品包覆率及粒子凝集試驗。在安全性的評估將利用細胞存活率方式確認載體對於細胞的傷害,並確認當載體進入體內循環時是否會造成溶血的現象。此外,比較其釋放速率與經皮穿透行為,並利用雷射共軛焦顯微鏡觀察對皮膚穿透的程度及深度。並評估載體在以誘發動物皮膚表皮增生及癌前皮膚模式下其穿透行為。在物化性質的結果,相同組成下粒徑表現,乙醇微脂粒系統中明顯小於微脂粒系統。此外phosphatidyethanolamine(PE)/cholesterol/sodium stearate在莫耳比為2:1:2.5條件下,在微脂粒及乙醇微脂粒系統下其包覆率,分別為29 %,66 %。在經皮穿透行為利用共軛焦顯微鏡觀察PpIX停留於皮膚的含量,乙醇微脂粒系統中明顯小於微脂粒系統,但是在藥物包覆率與經皮穿透能力之間並非呈現正相關。我們也確認乙醇微脂粒(PE),在体內試驗下可成功的將ALA經皮傳遞並轉換成PpIX於皮膚表皮增生及癌前皮膚,此外也證實可成功降低增生皮膚其TNF-α之表現。
Photodynamic therapy with 5-aminolevulinic acid (ALA) is a non-invasive technique which an alternative therapy for many skin disease. Indeed, ALA is a precursor of the photosensitizer, protoporphyrin IX (PpIX), formed in vivo after the exogenous application of ALA. When PpIX is activated by light, photochemical reaction may cause malignant and non-malignant tissue to be destroyed. However, ALA molecules are zwitterions which have the limitation of poor penetration through cell membrane or skin. The properly design-carrier including liposome and ethosome was used to improve the penetration problem for topical delivery ALA. The physicochemical properties including particle size, zeta potential, drug entrapment and particle aggregation were used to choose an adequate carrier. The safety of carrier was evaluated with regard to cellular cytotoxicity and erythrocyte hemolysis. Accordingly, the release rates and skin penetration of ALA from carriers to examine the penetration behavior. The images from confocal laser scanning microsopy (CLSM) were observed for confirming the potency and deliver depth of the skin. Further, we used the platform of skin hyperproliferation and pre-cancer skin model to evaluate the skin penetration behavior of carriers. The study presents physicochemical properties and penetration behavior between liposome and ethosome. The result showed that the vesicle size of the ethosomal system significantly smaller than that of liposomal system. Moreover, our findings indicated that a molar ratio of 2:1:2.5 phosphatidylcholine/cholesterol/sodium stearate represented high entrapment efficiencies in both the ethosomal and liposomal systems. In addition, results of CLSM indicated that the penetration ability of ethosomes was grater than that of liposomes in terms of PpIX deposition in the normal skin. However, there was no correlation between the entrapment efficiencies and penetration of PpIX into skin. We also confirmed that PE ethosomal carrier significantly improved the delivery of ALA and the formation of PpIX in both normal skin and epidermal hyperplasia, and the TNF-α level was reduced after the ALA-ethosomes were applied to treat psoriasis.
目錄

中文摘要i
英文摘要ii

壹、緒論1
一、光動力療法1
1.歷史1
2.原理3
3.光敏感物質4
4.光源6
5.ALA簡介8
二、藥物局部傳輸10
1.皮膚簡介10
1-1 皮膚構造10
1-2 表皮層(及角質層)之角色11
1-3 經皮傳遞途徑13
2.促進藥物穿透方式17
3.ALA劑型設計文獻回顧20
三、劑型設計21
1.微脂粒21
2.乙醇微脂粒24
四、皮膚疾病動物模式之建立27
五、研究目的28
貳、材料與方法29
一、試劑與儀器29
1.藥品與試劑29
2.劑型材料30
3.儀器31
4.細胞培養32
二、研究方法33
1.ALA分析方法之建立33
2.劑型設計34
2-1 劑型製備34
2-2 物化性質之測定35
2-2-1 粒徑35
2-2-2 介面電位36
2-2-3 藥品包覆率之測定36
2-2-4 粒徑經時變化之評估37
2-2-5 掃描式及穿透式電子顯微鏡之觀察37
2-2-6 式差熱量掃描之分析37
2-2-7 傅立葉轉換紅外光譜儀之分析38
2-3 處方安全性之評估38
2-3-1 細胞存活率38
2-3-2 溶血反應39
3.皮膚傳遞能力之評估40
3-1 體外穿透試驗40
3-2 雷射共軛焦顯微鏡之觀察43
4.皮膚疾病之誘發45
4-1 模擬皮膚增生之皮膚45
4-2 模擬癌前皮膚病變46
5.光動力療法47
5-1 儀器裝置47
5-2 光照程序47
5-3 以色差儀觀察光照對皮膚刺激之影響48
6.療效評估48
6-1 細胞毒殺試驗48
6-2 皮膚增生之測量48
6-3 Tumor necrosis factor-alph (TNF-α)之測量49
7.統計分析49
參、結果與討論50
一、ALA分析方法及確效50
二、微脂粒52
1.物化性質評估之結果52
1-1 添加不同磷脂質的影響52
1-2 添加膽固醇的影響53
1-3 添加不同界面活性劑的影響53
1-4 添加不同濃度sodium stearate (SS)的影響54
1-5 粒徑經時變化之評估54
1-6 掃描式及穿透式電子顯微鏡之觀察55
2.處方安全性評估之結果56
2-1 細胞存活率之評估56
2-2 溶血反應之評估57
3.微脂粒穿透能力評估之結果58
3-1 釋放速率與體外穿透試驗58
3-2 經皮穿透機轉之探討59
3-3 雷射共軛焦顯微鏡之觀察60
4.討論61
4-1 物化性質之探討61
4-2 處方安全性之評估64
4-3 微脂粒體外穿透能力之評估65
4-4 結論67
三、乙醇微脂粒68
1.物化性質評估之結果68
1-1 粒徑,介面電位,包覆率68
1-2 粒徑經時變化之評估68
1-3 式差熱量掃描之結果69
1-4 傅立葉轉換紅外光譜儀之結果70
1-5 穿透式電子顯微鏡之觀察73
2.安全性評估之結果73
3.體外釋放速率及體外穿透試驗之結果74
4.體內穿透能力評估之結果(微脂粒和乙醇微脂粒)74
4-1 雷射共軛焦顯微鏡之觀察(微脂粒)75
4-2 雷射共軛焦顯微鏡之觀察(乙醇微脂粒)76
5.光照影響之結果77
5-1 以色差儀觀察光照對皮膚刺激性之影響.77
5-2 雷射共軛焦顯微鏡之觀察78
6.討論80
6-1 物化性質之比較(微脂粒和乙醇微脂粒)80
6-2 穿透行為之比較(微脂粒和乙醇微脂粒)82
6-3 光照之影響85
6-4 結論86
四、疾病模式之評估87
1.病理切片觀察之結果87
2.體外穿透行為評估之結果88
3.體內穿透行為評估之結果90
3-1 雷射共軛焦顯微鏡之觀察(模擬皮膚增生)90
3-2 雷射共軛焦顯微鏡之觀察(模擬癌前皮膚)91
4.療效評估之結果92
4-1 處方對於基底細胞癌毒性之評估92
4-2 處方對於皮膚增生之評估93
4-3 處方對於Tumor necrosis factor-alph (TNF-α)之評估94
5.討論95
5-1 誘發表皮增生之動物模式95
5-2 體外穿透疾病皮膚之行為評估96
5-3 體內穿透疾病皮膚之行為評估97
5-4 療效評估97
5-5 結論99
肆、研究結論及未來展望100
伍、參考文獻101
陸、發表之論文108

附圖目錄
附圖 1 光動力療法發展之歷史2
附圖 2 光化學反應之機轉3
附圖 3 光源傳遞的形式7
附圖 4 ALA在人體代謝之流程9
附圖 5 皮膚組織構造圖10
附圖 6 表皮層之微觀11
附圖 7 角質層細胞內之微觀12
附圖 8 藥物經皮傳遞進入角質細胞之傳輸途徑13
附圖 9 被動擴散之示意圖16
附圖 10 促進藥物穿透行為之形式17
附圖 11 微脂粒多層膜之卡通圖21
附圖 12 微脂粒之基本組成23
附圖 13 傳統微脂粒與可形變微脂粒其構造之比較24
附圖 14 乙醇脂質體經皮膚角質層穿透可能之機轉25
附圖 15 衍生化之化學機轉33
附圖 16 帶電粒子其周圍離子的分布36
附圖 17 MTT 於活體細胞粒線體還原過程38
附圖 18 Franz直立式穿透裝置40
附圖 19 共軛焦顯微鏡原理43
附圖 20 Sulforhodamine B之結構式44
附圖 21 誘發癌前皮膚之實驗概略圖46
附圖 22 PDT之儀器47
附圖 23乙醇微脂粒系統經皮作用模式84
附表目錄
附表 1 已進入臨床試驗及已上市的光敏感物質5
附表 2 微粒系統的分類22
附表 3 常用的磷脂質材料之親水基(或頭基) 23
附表 4 常用的磷脂質之疏水基及其命名23
附表 5. 以乙醇微脂粒作為載體之應用26
附表 6 體外裝置條件之設定41
附表 7 穿透試驗所使用之障壁41

結果圖目錄
圖 1-1 ALA經衍生化之HPLC分析圖譜50
圖 1-2 ALA分析之檢量線51
圖 2-1 微脂粒PE/CH/SS包覆ALA之外觀55
圖 2-2 評估ALA以游離態及不同處方的微脂粒之細胞存活率56
圖 2-3 評估不同處方及濃度之微脂粒其對人類紅血球之溶血反應57
圖 2-4 評估ALA以游離態及不同處方的微脂粒處方經時變化圖58
圖 2-5 雷射共軛焦顯微鏡觀察在體外試驗下投與大白鼠皮膚24 h後,皮膚內所含的紅色螢光訊號60
圖 3-1 經式差熱量掃描之圖譜69
圖 3-2 經傅立葉轉換紅外光譜儀掃描之圖譜71
圖 3-3 經穿透式電子顯微鏡觀察乙醇微脂粒包覆ALA之外觀73
圖 3-4 評估ALA以游離態及乙醇微脂粒之細胞存活率73
圖 3-5 評估ALA以游離態及處方的乙醇微脂粒處方經時變化74
圖 3-6 以共軛焦顯微鏡觀察活體試驗下投與微脂粒裸鼠背部4小時後紅色螢光訊號之強度75
圖 3-7 以共軛焦顯微鏡觀察活體試驗下投與乙醇微脂粒裸鼠背部4小時後紅色螢光訊號之強度76
圖 3-8 以共軛焦顯微鏡觀察活體試驗下投與裸鼠背部4小時後搭配光照其紅色螢光訊號之強度78
圖 4-1 以光學顯微鏡觀察裸鼠皮之組織切片結果87
圖 4-2 比較PE乙醇微脂粒經不同穿透障壁之經時累積穿透量關係
圖89
圖 4-3 以共軛焦顯微鏡觀察活體試驗下經膠帶撕除模擬皮膚增生投與4小時後紅色螢光訊號之強度90
圖 4-4 以共軛焦顯微鏡觀察活體試驗下經TPA誘導之模擬癌前皮膚投與4小時後紅色螢光訊號之強度91
圖 4-5 經投藥處理24 h後評估有無光照對基底細胞癌存活率之響92
圖 4-6 經投藥處理24 h後基底細胞癌型態的改變93
圖 4-7 經皮投藥處理4 h後皮膚增生的改變93
圖 4-8 經投藥處理4小時後皮膚蛋白質所含TNF-α之含量比較94
結果表目錄
表 1-1 ALA同日間(intra-day)檢量線確效51
表 1-2 ALA異日間(inter-day)檢量線確效51
表 2-1 不同磷脂質之微脂粒其物化性質變化52
表 2-2 添加膽固醇至不同磷脂質其物化性質變化53
表 2-3 添加不同界面活性劑之物化性質變化53
表 2-4 添加不同濃度sodium stearate之物化性質變化54
表 2-5 微脂粒經時變化54
表 2-6 比較ALA在微脂粒與游離態(控制組)之釋放速率與經皮穿透速率58
表 2-7 評估ALA以游離態及微脂粒處方(PE/CH/SS)經過完整鼠皮、去角質皮膚、去脂質皮膚之經皮穿透速率59
表 3-1 ALA包覆於乙醇微脂粒之基本物化性質68
表 3-2 乙醇微脂粒經時變化68
表 3-3 經傅立葉轉換紅外光譜儀掃描所代表之訊號及官能基72
表 3-4 比較ALA在乙醇微脂粒與游離態(控制組)之釋放速率與經皮穿透速率74
表 3-5 以色差儀評估 PDT 光照對裸鼠皮膚的刺激性影響77
表 3-6 比較不同處方在PDT光照後前後皮膚內表現的PpIX含量79
表 4-1 比較PE ethosome經不同穿透障壁之累積穿透量及促進倍數88
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