臺灣博碩士論文加值系統

三環抗憂鬱藥 (tricyclic antidepressants, TCAs) 是最早被使用的一類抗憂鬱藥，主要用於治療情感性疾病，除此之外 TCAs 也具有止痛作用，是為用於治療周邊神經痛的第一線藥物。本實驗第一部分研究目的為評估局部投予 5 種 TCAs：mesoridazine、promazine、fluphenazine、doxepin 及 amitriptyline 之經皮吸收能力、皮膚止痛效果及皮膚投藥的安全性。實驗結果發現 fluphenazine 溶解度及皮膚的穿透吸收最低。在穿透皮膚之路徑解析方面，皮膚角質層會對 doxepin 造成吸收障礙，然而對 mesoridazine 及 promazine 則無顯著影響。在局部止痛測試中以 pin prick score 評估發現 mesoridazine 止痛效果較 promazine 及 doxepin 佳，mesoridazine (165 分鐘) 止痛所持續之時間相對於 promazine 及 doxepin 也較長。而在皮膚刺激試驗發現 promazine 及 doxepin 可能對皮膚造成受損現象，而 mesoridazine 則無明顯的皮膚損傷，綜合以上實驗可推斷 mesoridazine 為最具潛力成為皮膚的局部止痛劑的候選藥物。另外 amitriptyline 為臨床上最常使用之 TCAs 藥物，不過 amitriptyline 之副作用可能會造成心臟及中樞神經系統的毒性，一些憂鬱症的患者會服用過量 amitriptyline 企圖自殺，最後導致中毒死亡，目前臨床上以 intravenous lipid emulsion (ILE) 為解毒劑，但卻會導致一些副作用的發生。因此第二部分研究目的為製備不同奈米劑型以作為 amitriptyline 之中毒解毒劑，以選出最佳之中毒解毒劑。實驗結果 NE3 單層 nanoemulsion 所能 entrap amitriptyline 之百分比較高。在平均動脈壓及心跳方面 NE3 相對其它奈米劑型有更佳的改善效果。存活率方面投予市售解毒劑 intralipid 之存活率將近 50%，而投予 NE3 之存活率則可達 83.33%，相較之下投予 NE3 存活率比市售解毒劑 Intralipid 更佳，綜合以上實驗可推斷 NE3 相當有潛力可作為 amitriptyline 中毒之解毒劑。

Tricyclic antidepressants (TCAs) are the first antidepressants mainly apply in treatment of mood disorders. In addition, TCAs are also found to have efficacy in analgesia, which is the fist-line medication for treatment of peripheral neuralgia. The first part of the experiment was to assess topical application of the five TCAs: mesoridazine, promazine, fluphenazine doxepin and amitriptyline to evaluate their ability of transdermal delivery, topical analgesia and the safety of transdermal administration. Among five antidepressants in the in vitro experiment, fluphenazine showed the lowest solubility and total absorption percentage. To analysis the delivery pathway through the skin, the stratum corneum will lead to absorption barrier of doxepin, but no significant effect on mesopridazine and promazine. Topical analgesic test of TCAs was assessed by pin prick score. Mesoridazine showed stronger skin analgesia and prolonged duration of pain relief (165min) compared to promazine and doxepine. The skin irritation test demonstrated an evident barrier function deterioration and cutaneous erythema by promazine and doxepin treatment, whereas mesoridazine caused no obvious adverse effect by topical application. These study results suggested that mesoridazine is the most potential candidate for local analgesia. In addition, amitriptyline was the most commonly used TCA in clinical but it’s side effects can lead to cardiac and central nervous system toxicity. Some patients with depression even commit suicide with overdose amitriptyline. Intravenous lipid emulsion (ILE) is used as antidote of TCA clinically but it may lead to some side effects. Therefore, the second part of the study aims to assess the different nano-dosage form as antidote of amitriptyline poisoning. The study result showed NE3 which is single layer nanoemulsion can entrap a higher percentage of amitriptyline. In terms of mean arterial pressure and heart rate, NE3 lead to better improvement compared with other nano-dosage forms. The survival rate of the commercial antidote intralipid is nearly 50%. In contrast, the survival rate of NE3 was 83.33%, better than that of commercial antidote intralipid. In conclusion, the above study results suggest that NE3 has considerable potential as an antidote for amitriptyline poisoning.

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致謝...............................................................................................................................iii
中文摘要.......................................................................................................................iv
Abstract..........................................................................................................................v
總目錄..........................................................................................................................vii
圖目錄........................................................................................................................ xiii
表目錄..........................................................................................................................xv
前言................................................................................................................................1
第一章、緒論................................................................................................................2
第一部分：三環抗憂鬱藥之皮膚鎮痛能力評估 ................................................2
第一節、三環抗憂鬱藥 (tricyclic antidepressants, TCAs)..................................2
1、作用機轉 (mechanism of action)...........................................................2
2、藥物動力學 (pharmacokinetics)............................................................2
3、常見的副作用.........................................................................................3
4、治療用途 (therapeutic uses)...................................................................3
第二節、神經痛 (neuropathic pain).....................................................................5
1、中樞神經痛 (central neuropathic pain)..................................................5
2、周邊神經痛 (peripheral neuropathic pain) ............................................5
3、神經痛機制.............................................................................................6
第三節、皮膚 (skin).............................................................................................7
1、表皮層 (epidermis).................................................................................8
2、真皮層 (dermis) .....................................................................................9
3、皮下組織 (hypodermis) .........................................................................9
第四節、藥物穿透皮膚的途徑 ............................................................................9
1、直接穿透角質層蛋白質-脂質基質 (transcellular pathway)...............10
2、經細胞間隙的脂質層穿透 (intercelluar pathway)..............................10
3、經由附屬器官穿透 (transappendageal pathway)................................10
第五節、影響藥物經皮吸收的因素 ..................................................................11
1、皮膚的生理狀態...................................................................................11
2、藥物的特性...........................................................................................11
3、載體.......................................................................................................11
4、投予方式...............................................................................................11
第六節、促進藥物經皮吸收之方法 ..................................................................12
1、物理性促進方法...................................................................................12
2、化學性促進方法...................................................................................12
第二部分：三環抗憂鬱藥奈米解毒劑之開發 ..................................................13
第一節、藥物中毒 ..............................................................................................13
第二節、靜脈注射脂肪乳劑 (intravenous lipid emulsion, ILE).......................13
1、脂質乳劑簡介.......................................................................................13
2、脂質乳劑解毒作用機理.......................................................................14
第三節、脂質奈米微粒 (lipid nanoparticles)....................................................16
1、脂乳劑 (nanoemulsions, NEs) .............................................................16
2、固態脂質奈米微粒 (solid lipid nanoparticles, SLNs).........................16
3、奈米結構脂質載體 (nanostructured lipid carriers, NLCs)..................17
4、微脂粒 (liposomes)..............................................................................17
5、非離子微泡 (niosomes).......................................................................18
第四節、模式藥物 amitriptyline........................................................................19
第二章、研究動機與實驗設計..................................................................................20
第一節、研究動機 ..............................................................................................20
第一部分 ..............................................................................................................20
第二部分 ..............................................................................................................21
第二節、實驗設計與流程 ..................................................................................22
第一部分 ..............................................................................................................22
第二部分 ..............................................................................................................23
第三章、材料與方法..................................................................................................23
第一節、實驗試劑、醫療材料與儀器設備 ......................................................24
1、試劑與醫材...........................................................................................24
2、儀器設備...............................................................................................27
第二節、實驗方法 ..............................................................................................29
第一部分 ..............................................................................................................29
1、藥物去鹽類之前處理...........................................................................29
2、藥物之 HPLC 分析條件建立.............................................................29
3、藥物之物化性質測試及分子特性模擬...............................................30
3-1、物化性質模擬....................................................................................30
3-2、溶解度測試........................................................................................30
3-3、HPLC 之容積因子 (capacity factor, log K’)...................................30
3-4、油水分配係數 (partition coefficient, log P).....................................31
4、藥物體外經皮吸收實驗及皮膚製備...................................................31
4-1、藥物體外經皮吸收累積穿透量........................................................31
4-2、藥物體外經皮吸收皮內藥物含量分析............................................32
4-3、動物皮膚及其製備............................................................................33
4-3-1、未處理之裸鼠皮 (intact nude mouse skin)...................................33
4-3-2、未處理之豬皮 (intact pig skin).....................................................33
4-3-3、去角質層之皮膚 (stratum corneum (SC)-stripping skin).............33
4-3-4、去脂質皮膚 (de-lipid skin)............................................................33
4-3-5、去皮脂之皮膚 (de-sebum skin) ....................................................34
4-3-6、人工膜 ............................................................................................34
5、生體內皮內藥物含量測試...................................................................34
6、藥物之止痛活性測試...........................................................................35
7、皮膚安全性試驗...................................................................................35
7-1、皮膚表皮之水分散失量 (transepidermal water loss, TEWL).........35
7-2、色差計測定........................................................................................36
7-3、表皮酸鹼度測定................................................................................36
7-4、組織病理學 (histopathology) ...........................................................36
8、數據分析及統計方法...........................................................................37
第二部分 ..............................................................................................................38
1、奈米劑型製備.......................................................................................38
1-1、NEs、SLNs 及 NLCs 之製備........................................................38
1-2、Liposomes 之製備............................................................................40
1-3、Niosomes 之製備..............................................................................41
2、奈米劑型之物化性質...........................................................................42
2-1、顆粒粒徑 (size) 測定.......................................................................42
2-2、表面電位 (zeta potential, ZP) 測定.................................................42
2-3、親合力測定........................................................................................42
2-4、疏水性試驗........................................................................................43
2-5、示差熱掃描分析儀 (differential scanning calorimetry, DSC).........43
3、藥物包埋率測定...................................................................................43
4、劑型包覆藥物之體外釋放試驗...........................................................44
4-1、未重建劑型包覆藥物之體外釋放試驗............................................44
4-2、重建劑型包覆藥物之體外釋放試驗................................................44
5、生物分子交互分析微量熱儀 (isothermal titration calorimetry, ITC) 44
6、穿透式電子顯微鏡 (transmission electron microscope, TEM) 觀察劑
型型態.........................................................................................................45
7、藥物與劑型之 in vivo 試驗 ................................................................45
7-1、觀察 in vivo 和 ex vivo 生物影像..................................................45
7-2、藥物動力學實驗 (pharmacokinetics)...............................................46
7-3、藥效學實驗 (pharmacodynamics)....................................................47
7-4、存活率 (survival rate).......................................................................47
8、數據分析及統計方法...........................................................................47
第四章、結果..............................................................................................................48
第一部分 ..............................................................................................................48
1、藥物之物化性質模擬及測試...............................................................48
2、藥物體外經皮吸收試驗.......................................................................49
2-1、鹽類藥物在裸鼠皮與豬皮之經皮吸收試驗....................................49
2-2、去鹽類藥物在裸鼠皮膚之經皮吸收試驗........................................52
2-3、去鹽類藥物在豬皮之經皮吸收試驗................................................53
3、藥物穿透皮膚路徑探討.......................................................................54
3-1、不同方式處理裸鼠皮膚之經皮吸收試驗........................................54
3-2、不同方式處理豬皮膚之經皮吸收試驗............................................55
4、生體內皮內藥物含量...........................................................................56
5、藥物之止痛活性測試...........................................................................57
6、皮膚安全性測試...................................................................................59
7、組織病理學...........................................................................................61
第二部分 ..............................................................................................................63
1、奈米劑型之物化性質...........................................................................63
1-1、粒徑大小、粒徑分散係數及表面電位............................................63
1-2、親合力測定........................................................................................66
1-3、疏水性試驗........................................................................................69
1-4、示差熱掃描分析儀 (DSC) 分析 .....................................................70
2、藥物包埋率測定...................................................................................71
3、劑型包覆藥物之體外釋放試驗...........................................................72
3-1、未重建劑型包覆藥物之體外釋放試驗............................................72
3-2、重建劑型包覆藥物之體外釋放試驗................................................73
4、生物分子交互分析微量熱儀 (ITC)....................................................74
5、穿透式電子顯微鏡 (TEM) 觀察劑型型態........................................76
6、藥物與劑型之 in vivo 試驗 ................................................................78
6-1、觀察 in vivo 和 ex vivo 生物影像..................................................78
6-2、藥物動力學實驗 (pharmacokinetics)...............................................82
6-3、藥效學實驗 (pharmacodynamics)....................................................83
6-4、存活率 (survival rate).......................................................................85
第五章、討論..............................................................................................................86
第一部分 ..............................................................................................................86
第二部分 ..............................................................................................................89
第六章、結論..............................................................................................................94
第一部分 ..............................................................................................................94
第二部分 ..............................................................................................................95
第八章、參考文獻......................................................................................................96
附錄............................................................................................................................109


圖目錄
圖一、三環抗憂鬱藥之結構式 4
圖二、中樞神經痛及中樞周邊神經痛示意圖 6
圖三、皮膚構造示意圖 7
圖四、表皮層示意圖 8
圖五、藥物進入皮膚途徑示意圖 10
圖六、脂質奈米微粒結構圖 17
圖七、微脂粒 (liposomes) 圖 18
圖八、非離子微泡 (niosomes) 圖 19
圖九、Franz diffusion cell 裝置示意圖 32
圖十、經皮吸收之藥物累積穿透量及皮內藥物含量 51
圖十一、體內經皮吸收之皮內藥物含量 56
圖十二、各藥物止痛效果與止痛所能持續時間之結果 58
圖十三、皮膚水分散失、紅腫程度及酸鹼度之結果 60
圖十四、藥物之皮膚安全性試驗 H/E stain 結果 62
圖十五、奈米劑型能 entrap 藥物之百分比 68
圖十六、奈米劑型之疏水性試驗結果 69
圖十七、奈米劑型之 DSC 圖 70
圖十八、未重建劑型包覆藥物之體外釋放試驗 72
圖十九、重建劑型包覆藥物之體外釋放試驗 73
圖二十、生物分子交互分析微量熱儀結果 75
圖二十一、奈米劑型之 TEM 圖 77
圖二十二、生物體內動態分佈活體影像 78
圖二十三、各器官之影像 80
圖二十四、各器官經劑型亮度校正後之影像 81
圖二十五、經不同奈米劑型作為解毒劑在各器官之藥物濃度分佈情形 82
圖二十六、藥效學實驗結果圖 84
圖二十七、存活率 85
附圖一、Mesoridazine besylate 1H NMR 光譜 111
附圖二、Mesoridazine 1H NMR 光譜 111
附圖三、Promazine hydrochloride 1H NMR 光譜 112
附圖四、Promazine 1H NMR 光譜 112
附圖五、Fluphenazine dihydrochloride 1H NMR 光譜 113
附圖六、Fluphenazine 1H NMR 光譜 113
附圖七、Doxepin hydrochloride 1H NMR 光譜 114
附圖八、Doxepin 1H NMR 光譜 114
附圖九、Amitriptyline hydrochloride 1H NMR 光譜 115
附圖十、Amitriptyline 1H NMR 光譜 115

 
表目錄
表一、Intralipid處方成分比例 14
表二、五種藥物之 HPLC 分析條件 29
表三、NEs 系列劑型處方成分比例 38
表四、SLNs 系列劑型處方成分比例 39
表五、NLCs 系列劑型處方成分比例 39
表六、Liposomes 劑型處方成分比例 40
表七、Niosomes 系列劑型處方成分比例 41
表八、藥物之物化性質 48
表九、15 mM 藥物懸浮狀態於 24 小時後裸鼠皮膚之穿透速率、皮內藥物含量及穿透百分比 52
表十、藥物於飽和狀態於 24 小時後裸鼠皮膚之皮內藥物含量、滲透係數及穿透百分比 52
表十一、15 mM 藥物懸浮狀態於 24 小時後豬皮膚之穿透速率、皮內藥物含量及穿透百分比 53
表十二、藥物於飽和狀態於 24 小時後豬皮膚之皮內藥物含量、滲透係數及穿透百分比 53
表十三、藥物在不同狀態裸鼠皮膚及人工膜之穿透速率 54
表十四、藥物在不同狀態裸鼠皮膚之皮內藥物含量 54
表十五、藥物在不同狀態豬皮膚及人工膜之穿透速率 55
表十六、藥物在不同狀態豬皮膚之皮內藥物含量 55
表十七、NEs 系列劑型之物化性質比較 64
表十八、SLNs 系列劑型之物化性質比較 64
表十九、NLCs 系列劑型之物化性質比較 65
表二十、Liposomes 劑型之物化性質比較 65
表二十一、Niosomes 系列劑型之物化性質比較 65
表二十二、藥物在處方中的包埋率 71
表二十三、各器官之螢光百分比 80

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