臺灣博碩士論文加值系統

固態脂質奈米微粒 (SLN) 與奈米結構脂質載體 (NLC) 為新一代奈米微粒，並且是受到主要關注的新膠體藥物載體。本篇論文有二個研究目的。第一個是以 psoralens 為模式藥物，以 SLN 和 NLC 作為藥物載體，期待能發展促進 psoralens 穿透並且具有控制釋放能力的傳輸系統；第二個目的為開發能持續性釋放 tryptanthrin 並且有效毒殺細胞之傳輸系統。在第一部分局部投與 psoralens 的實驗中，SLN 與 NLC 平均顆粒粒徑分別為 ~300 nm和 ~200 nm 大小的奈米粒子，藉由測量載體的黏度、極性以及示差熱量掃描分析 (DSC) 等實驗方法，觀察 SLN 與 NLC 之物理化學性質。以 Tween 80 和大豆磷脂質 (SPC) 作為乳化劑的 NLC-Tw 除外，其他的奈米系統都屬於牛頓流體。依據 DSC 熱量分析圖中，發現了含有角鯊烯的 NLC，由於液體油脂核心脂質非完美晶型結構造成粒徑縮小，使得 Precirol 熔點由原來 58 ℃ 降低至 55 ℃。以治療乾癬的三種 psoralen 的衍生物包覆於 SLN、NLC評估其穿透的能力，結果顯示 psoralens 穿透皮膚的能力高至低為 8-methoxypsoralen (8-MOP) > 5-methoxypsoralen (5-MOP) > 4,5’,8-trimethylpsoralen (TMP)。載體 NLC 既能促進藥物的穿透並且持續的釋放藥物，其中 NLC-Tw 運載 8-MOP 和乳劑相比，提高了 2.4 倍的穿透速率，遠勝過於傳統的乳劑。實驗亦透過重複剝除膠帶方式，形成表皮層過度增生類似乾癬病灶的皮膚作為穿透障壁，透過動物模型能用以預測載體應用在疾病的皮膚時的穿透能力。而第二部分以發展 tryptanthrin 之注射劑為其目的，結果發現 NLC 平均顆粒粒徑小於 SLN，並且藥物分配至 NLC 含量多，提高了 NLC 的釋放 tryptanthrin 的速率。NLC 系統能持續性的釋放藥物並且不會造成突釋的現象，以混合 squalene 與 Compritol 的 NLC-C 釋放率最高，毒殺效果最好。共軛焦雷射光掃瞄顯微鏡影像圖証實了，癌細胞能將處方胞飲入細胞質而毒殺細胞。這些結果顯示 SLN 以及 NLC 是很有潛力的藥物載體，未來或許能作為局部投與皮膚傳輸系統或者注射劑方面藥物之應用。

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are the new generation of nanoparticulate active substance vehicles and are attracting major attention as novel colloidal drug carriers. There are two purposes of this study. The first, we develop SLN and NLC, the nanoparticulate lipid based drug carriers, with increased skin permeation and controlled release properties for psoralens. The second, we investigate sustained release properties for tryptanthrin of nanoparticles and cytotoxicity of its tryptanthrin delivery system. For topical psoralen delivery (part I), SLN and NLC showed mean particle size of ~300 and ~200 nm respectively. Viscosity, polarity, and differential scanning calorimetry (DSC) studies were performed to characterize physicochemical properties of SLN and NLC. The viscosity of all nanoparticulate systems exhibited Newtonian behavior except NLC with Tween 80 and soybean phospholipids as the emulsfiers (NLC-Tw). According to the DSC thermograms, the melting peak of Precirol was shifted from 58 °C to 55 °C after incorporating squalene into the solid lipid cores (NLC) which suggests the defects in the crystalline lattice of the lipid cores and the smaller particle size. Three psoralen derivatives for psoriasis treatments were loaded in SLN and NLC for examining their skin permeation. The permeability of psoralens increased in the order of 8-methoxypsoralen (8-MOP) > 5-methoxypsoralen (5-MOP) > 4,5’,8-trimethylpsoralen (TMP). Both enhanced permeation and sustained release of psoralen delivery could be achieved by NLC. The in vitro permeation showed that NLC-Tw increased the 8-MOP flux 2.4 times over conventional emulsion. The hyperproliferative or psoriasis-like skin reproduced by repeated abrogation was also used as a permeation barrier. The animal model can predict the skin targeting ability of a drug applied on a disordered skin. For injection use tryptanthrin delivery (part II), NLC showed mean particle size lower and higher partition coefficient than SLN, thus increased the tryptanthrin release rate of NLC delivery system. NLC supplied sustained release of tryptanthrin delivery without burst release. Especially NLC-C which mixed squalene and Compritol as lipid materials showed highest released rate and best cytotoxicity effect. The images of confocal laser scanning microscopy confirmed that drug internalization into cell could be enhanced by the endocytosis of NLC. These results demonstrated that SLN and NLC can potentially be exploited as drug carrier systems for topical and intravenous use in the future.

總目錄
誌謝............................................................................................................................... I
中文摘要......................................................................................................................II
英文摘要.................................................................................................................... III
總目錄..........................................................................................................................V
表目錄..........................................................................................................................X
圖目錄........................................................................................................................ XI
縮寫表......................................................................................................................XIV
引言...............................................................................................................................1
第壹章 文獻回顧.......................................................................................................2
第一節 固態脂質奈米微粒...................................................................................2
1.1 固態脂質奈米微粒的組成..........................................................................2
1.2 奈米結構脂質載體的類型..........................................................................6
1.2.1 缺陷型奈米結構脂質載體...................................................................6
1.2.2 無定形型奈米結構脂質載體...............................................................6
1.2.3 複合型奈米結構脂質載體...................................................................7
1.3 固態脂質奈米微粒與奈米結構脂質載體的應用......................................7
第二節 藥物投與途徑...........................................................................................8
2.1 皮膚的簡介..................................................................................................8
2.2 藥物穿透皮膚的途徑................................................................................10
第貳章 乾癬之經皮吸收用藥的文獻回顧............................................................. 11
第一節 乾癬的簡介.............................................................................................11
第二節 乾癬的局部治療方式.............................................................................14
2.1 煤焦油........................................................................................................14
2.2 恩酚............................................................................................................15
2.3 甲氨蝶呤....................................................................................................16
2.4 類固醇類藥物............................................................................................17
2.4.1 Clobetasol propionate........................................................................18
2.4.2 Betamethasone....................................................................................19
2.4.3 Halobetasol propionate......................................................................21
2.5 維他命 D3 類似物....................................................................................21
2.5.1 Calcipotriol .........................................................................................22
2.5.2 Tacalcitol .............................................................................................23
2.5.3 Maxacalcitol........................................................................................23
2.5.4 Calcitriol .............................................................................................23
2.6 維他命 A 酸類藥物..................................................................................24
2.7 中草藥青黛的局部療法............................................................................26
第三節 光療法.....................................................................................................26
3.1 紫外線 B 光照射療法..............................................................................26
3.2 Psoralens 合併紫外線 A 光照射療法...................................................27
3.3 光動力學療法............................................................................................28
3.3.1 5-Aminolaevulinic acid ......................................................................28
3.3.2 孟加拉玫瑰素.....................................................................................30
第四節 合併療法.................................................................................................31
第五節 模式藥物.................................................................................................34
5.1 Psoralens ....................................................................................................34
5.2 Tryptanthrin..............................................................................................35
第六節 研究動機與目的.....................................................................................37
第參章 實驗材料與方法.........................................................................................38
第一節 實驗材料.................................................................................................38
1.1 試劑與醫材................................................................................................38
1.2 實驗儀器....................................................................................................40
第二節 Psoralens 脂質奈米微粒實驗方法.......................................................41
2.1 藥物的水中飽和溶解度試驗....................................................................41
2.2 容積因數試驗............................................................................................41
2.3 脂乳劑的製備方法....................................................................................42
2.4 固體脂質奈米微粒製備方法....................................................................42
2.5 奈米結構脂質載體製備方法....................................................................42
2.6 劑型的基本性質試驗................................................................................43
2.6.1 粒徑測定.............................................................................................43
2.6.2 表面電位測定.....................................................................................43
2.7 示差熱量掃描分析儀................................................................................43
2.8 劑型的疏水性實驗....................................................................................44
2.9 劑型之黏度與剪切率之關係....................................................................44
2.10 體外實驗..................................................................................................45
2.10.1 動物皮膚的取得方式.......................................................................45
2.10.2 建立乾癬病灶動物模式...................................................................45
2.10.3 體外實驗裝置...................................................................................45
2.10.4 體外穿透實驗步驟...........................................................................46
2.11 體外釋放實驗步驟...................................................................................46
2.11.1 Psoralens 飽和溶解度體外穿透實驗.............................................47
2.11.2 Psoralens 過飽和溶解度體外穿透實驗.........................................47
2.12 表皮增生的皮膚組織切片檢體製備方法..............................................47
2.12.1 皮膚組織檢體製備...........................................................................47
2.12.2 Mayer hematoxylin and Eosin stains 染色法...............................47
2.13 Psoralens 之 HPLC 分析條件.............................................................48
2.14 統計方法..................................................................................................48
第三節 Tryptanthrin 脂質奈米微粒實驗方法.................................................49
3.1 分配係數試驗............................................................................................49
3.2 脂乳劑製備方法........................................................................................49
3.3 固態脂質奈米微粒製備方法....................................................................50
3.4 奈米結構脂質載體製備方法....................................................................50
3.5 劑型的基本性質試驗................................................................................50
3.6 體外釋放實驗............................................................................................50
3.7 細胞實驗....................................................................................................50
3.7.1 細胞培養.............................................................................................50
3.7.2 細胞檢量線.........................................................................................51
3.7.3 Tryptanthrin 細胞毒性實驗..............................................................51
3.8 共軛焦雷射掃描顯微鏡............................................................................52
3.9 Tryptanthrin 之HPLC 分析條件...........................................................52
3.10 統計方法..................................................................................................52
第肆章 實驗結果與討論.........................................................................................53
第一節 Psoralens 類奈米微粒之實驗結果.......................................................53
1.1 劑型的基本性質........................................................................................53
1.2 示差熱量掃描分析儀................................................................................55
1.3 劑型的黏度檢測........................................................................................57
1.4 劑型的疏水性試驗....................................................................................59
1.5 Psoralens 的容積因數..............................................................................60
1.6 Psoralens 之體外實驗..............................................................................60
1.7 Psoralens 類脂質奈米微粒之綜合討論..................................................66
第二節 Tryptanthrin 奈米微粒之實驗結果.....................................................71
2.1 劑性基本性質............................................................................................71
2.2 Tryptanthrin 分配係數............................................................................73
2.3 Tryptanthrin 之釋放................................................................................74
2.4 Tryptanthrin 細胞毒性實驗....................................................................75
2.5 共軛焦雷射光掃瞄顯微鏡觀察乳癌細胞攝入劑型的情形....................78
2.6 Tryptanthrin 脂質奈米粒子之綜合討論................................................81
第伍章 結論.............................................................................................................85
第陸章 參考文獻.....................................................................................................86



表目錄
表一 製備固態脂質奈米微粒常用的脂質.................................................................3
表二 製備固態脂質奈米微粒常用的乳化劑.............................................................4
表三 乾癬的局部治療方式.......................................................................................33
表四 模式藥物化學結構式.......................................................................................36
表五 Psoralens 之高效能液相層析儀移動相比例.................................................48
表六 觀察 SLN、NLC 以及脂乳劑粒徑與表面電位之變化...............................54
表七 Psoralens 的容積因數.....................................................................................60
表八 Psoralens 容積因數與溶解度表現之綜合比較表.........................................68
表九 不同固態脂質 Compritol 與 Precirol 組成之 SLN、NLC 之奈米粒子粒
徑與表面電位比較表.....................................................................................72
表十 為處方 SLN、NLC 以及脂乳劑中 tryptanthrin 的油水分配係數..........73

圖目錄
圖一 儲存期間 SLN 的內部脂質結構轉變結構而排擠藥物的示意圖.................5
圖二 奈米結構脂質載體三種類型.............................................................................6
圖三 典型人體皮膚構造縱切面圖.............................................................................9
圖四 藥物穿透角質層的三種途徑...........................................................................10
圖五 典型乾癬病灶影像圖.......................................................................................12
圖六 (A) 正常皮膚與 (B) 乾癬病灶皮膚組織切片圖..........................................13
圖七 Anthralin 結構式............................................................................................15
圖八 Methotrexate 的結構圖..................................................................................16
圖九 Clobetasol propionate 結構圖........................................................................18
圖十 Hydrocortisone 結構圖..................................................................................19
圖十一 Triamcinolone 結構圖................................................................................20
圖十二 Betamethasone 結構圖...............................................................................20
圖十三 Betamethasone dipropionate 結構圖........................................................20
圖十四 Betamethasone valerate 結構圖................................................................20
圖十五 Halobetasol propionate 結構圖..................................................................21
圖十六 Calcipotriol 結構圖....................................................................................22
圖十七 Tacalcitol 結構圖........................................................................................23
圖十八 Maxacalcitol 結構圖...................................................................................24
圖十九 Calcitriol 結構圖.........................................................................................24
圖二十 Tazarotene 代謝圖......................................................................................25
圖二十一 Psoralens 作用的機轉圖.........................................................................27
圖二十二 (A) Protoporphyrin IX (B) 5-Aminolaevulinic acid 結構圖................29
圖二十三 Rose Bengal 結構圖................................................................................30
圖二十四 直立式擴散裝置構造圖...........................................................................46
圖二十五 單純 Precirol、劑型 SLN、物理混合物以及含藥的 SLN 中 Precirol
熔點之 DSC 圖譜..................................................................................55
圖二十六 NLC-PF 劑型、物理混合物與含藥的劑型之 Precirol 熔點 DSC 圖譜..............................................................................................................56
圖二十七 NLC-Tw 劑型及其物理混合物與含藥的劑型中 Precirol 熔點之 DSC 圖譜................................................................................................56
圖二十八 不同系統之流變性質曲線圖 (A) 剪切應力與剪切率關係圖 (B) 黏度與剪切率關係圖......................................................................................58
圖二十九 以尼羅河紅螢光強度判斷 SLN、NLC-PF、NLC-Tw 與脂乳劑系統之疏水性的差異..........................................................................................59
圖三十 以正常裸小鼠皮膚作為穿透障壁 SLN、NLC-PF、NLC-Tw 與脂乳劑 之 8-MOP 經時累積穿透量曲線比較圖.............................................61
圖三十一 以正常裸小鼠皮作為穿透障壁之 8-MOP、5-MOP 以及 TMP 於不 同奈米系統中穿透速率柱狀比較圖......................................................62
圖三十二 顯微鏡影像下觀察皮膚組織縱切面比較圖 (A) 未處理正常裸小鼠皮膚組織切面圖 (B) 膠帶撕除後具乾癬病灶的裸小鼠皮膚組織切面圖..................................................................................................................63
圖三十三 正常裸小鼠皮膚和乾癬病灶裸小鼠皮膚作為穿透障壁之SLN、NLC-PF、NLC-Tw 與脂乳劑 8-MOP 穿透速率柱狀比較圖.........64
圖三十四 比較 SLN、NLC-PF、NLC-Tw 與脂乳劑以及水溶液控制組之 8-MOP 釋放百分率曲線比較圖...........................................................65
圖三十五 處方 SLN、NLC 以及脂乳劑於人工膜釋放實驗中 tryptanthrin 之經時累積釋放趨勢比較圖......................................................................74
圖三十六 觀察投與不同劑量的處方 SLN、NLC 與脂乳劑之乳癌細胞於 (A) 24小時 (B) 48 小時之細胞存活率柱狀比較圖.......................................76
圖三十七 觀察不同時間點投與 tryptanthrin (A) 5.75 μM (B) 11.5 μM 兩種濃度的 SLN、NLC 以及脂乳劑之乳癌細胞存活率柱狀比較圖.........77
圖三十八 以共軛雷射光掃瞄顯微鏡觀察乳癌細胞投與含有 SB (5.2 μM) 處方NLC-C 與水溶液控制組 24 小時後細胞攝入情形圖.......................79
圖三十九 以共軛雷射光掃瞄顯微鏡觀察乳癌細胞投與含有 SB (10.4 μM) 處方NLC-C 與水溶液控制組 24 小時後細胞攝入情形圖.......................80
圖四十 藥物聚集於 SLN 脂質外殼層之示意圖...............................................82

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