含有環糊精之新式皮克林乳劑在布比卡因經皮傳輸之研究

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研究生：	胡濬文 Hu, Jiun-Wen
論文名稱：	含有環糊精之新式皮克林乳劑在布比卡因經皮傳輸之研究 Novel Cyclodextrin-Based Pickering Emulsions for Bupivacaine Topical Delivery
指導教授：	朱一民 Chu, I-Ming
口試委員:	林山陽 Lin, Shan-Yang 王藹君 Wang, Ae-June 邱信程 Chiu, Hsin-Cheng 方嘉佑 Fang, Jia-You
學位類別：	博士 Doctor
系所名稱：	工學院 - 化學工程學系 Department of Chemical Engineering
論文出版年：	2018
畢業學年度：	106
語文別：	中文
論文頁數：	127
中文關鍵詞：	皮克林乳劑、環糊精、布比卡因、鑲嵌聚合物、局部給藥、經皮傳輸
外文關鍵詞：	Pickering emulsions, cyclodextrins, bupivacaine, inclusion complex, topical delivery
相關次數：	點閱：3 下載：0
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布比卡因 (Bupivacaine) 是美國 FDA 許可的局部麻醉劑中藥效最長的藥物，其止痛效果可以長達 18 到 24 小時。但是其對心臟的毒性以及對神經系統損害的副作用也廣為人知。藉由經皮方式給予藥物可以降低血中的布比卡因濃度進而降低副作用。本研究旨在利用含有環糊精的皮克林乳劑配方，使其具有良好穩定性以及使布比卡因能達到持續穿入且停留在皮膚的效果，達到減低藥物在全身循環中的濃度。
皮克林乳劑配方的組成包括溶解藥物的油相成分，界面層的固體顆粒及其他界面活性物質。研究中分別使用直鏈狀、環狀結構以及三酸甘油酯等三種不同結構的油來溶解布比卡因，並且選擇環糊精與油相分子形成的固體粒子作為界面關鍵成分來製備皮克林乳劑。添加界面活性劑來調整配方表面特性以延長安定性。利用動態光散射儀來分析配方的粒徑，並且使用掃描式電子顯微鏡來觀察配方的微觀結構。藉由流變儀來分析配方的流變特性。使用 Franz 垂直式滲透裝置進行體外藥物釋放試驗與皮膚滲透試驗。運用共軛焦雷射掃描顯微鏡來探討皮克林乳劑穿透皮膚的機制。最後，利用 von Frey 試驗來評估配方在動物身上的麻醉效果。
環糊精的空腔大小與油相的選擇會影響環糊精與油相的聚合物生成效果，進而影響皮克林乳劑配方的安定性。此聚合物會在油滴外層形成一層殼狀結構，即使配方經過乾燥，仍可觀察到完整的球狀結構。在皮膚滲透試驗中，穿透過皮膚的累積藥物量與穿透速率，由高到低為環狀結構油 >直鏈狀油 > 三酸甘油酯。但是在給藥 24 小時之後的皮內藥物累積量，卻是直鏈狀油 > 環狀結構油 > 三酸甘油酯。
添加界面活性劑可以降低配方黏度並延長配方安定性，但是卻會降低皮膚滲透效果以及提高皮膚刺激性的風險。提高環糊精濃度會因為 bridge effect 而提高配方黏度，並且能減緩粒徑變動的幅度。藉由調整環糊精濃度來調整界面特性應為較適當的延長安定性之方式。
混合直鏈狀油與環狀結構油做為配方之油相，同樣也有延長安定性的效果。此外，其穿透皮膚以及累積在皮膚內的藥量都較只用一種油的配方高。利用局部給藥的方式在大鼠背部給予布比卡因皮克林乳劑，會比利用皮下注射方式給予布比卡因溶液有更長的麻醉作用時間。我們相信此新式的皮克林乳劑能夠在經皮給藥的麻醉應用上有很好的發展潛力。

Bupivacaine (BPC) is currently the longest acting local anesthetic approved by the FDA, with an analgesic effect lasting up to 18 to 24 hours. However, BPC has several well-documented side effects, such as cardiovascular disorders and neurological disturbances. Through applying it topically to reduce the concentration of BPC in the blood, these side effects could be reducing. In this work, we have developed a cyclodextrin-based Pickering emulsions formulation to effectively maintain sustained skin permeation of bupivacaine and reduce the drug concentration in systemic circulation.
As to the oil phase, different structures of oil, including linear-chain, ring-structure, and triglyceride were selecte to dissolve BPC, and cyclodextrin was chose as a key component forming Pickering emulsions. Surfactants were added to modify the interface properties for prolonging stability. We detected the particle size and observed appearance by dynamic light scattering (DLS) and scanning electron microscopy (SEM), respectively. We assayed the rheological behavior by rheometer. We used Franz diffusion cell to perform in vitro drug release test and in vitro skin permeation study. The skin penetration mechanisms of the Pickering emulsions were further visualized by confocal laser scanning microscopy (CLSM). At least, von Frey filament test was used to measure the in vivo anesthetic effect.
The cavity space of cyclodextrin and oil structure affect cyclodextrin-oil complex production, eventually influence the stability of Pickering emulsion formulations. In addition, the shell of cyclodextrin-oil inclusion complex around the o/w droplets is so stable that it maintains the spherical structure even under strict drying process. The accumulation amount and flux of BPC permeating through skin were as follow, ring-structure oil > linear-chain oil > triglyceride oil. However, the amounts of BPC retained in the skin after 24 hours exposure were not the same, the order was linear-chain oil > ring-structure oil > triglyceride oil.
Although adding surfactants could reduse the viscosity and prolong the stability of Pickering emulsions, it retards the skin permeability and increases the risks of skin irritation. Increasing the CD concentration could enhance the viscosity by bridge effect and ease off the particle size change. It was a suitable way to modify the interface properties of Pickering emulsions for prolonging the stability.
Mixing linear-chain oil and ring-structure oil as oil phase could also extend the stability. Moreover, it could achieve higher BPC amount both in passing through and in skin retaining than any single type oil phase. Applying BPC Pickering emulsion topically on rats’ back keeps longer anesthetic effect than applying subcutaneously injection of BPC solution. We believe that this novel Pickering emulsion formulation has potential in providing effective topical anesthesia.

中文摘要    I
Abstract    III
誌謝    V
總目錄    VI
圖目錄    XI
表目錄    XIII
縮寫表    XV
第壹章 緒言    1
第貳章 文獻回顧    3
第一節 神經痛的市售治療藥物    3
第二節 局部麻醉劑    4
1　作用原理與分類    4
2　布比卡因 (Bupivacaine, BPC)    5
第三節 經皮傳輸系統    6
1　皮膚簡介    6
2　經皮給藥系統的優點與缺點    8
3　經皮傳輸途徑    9
4　經皮吸收原理    11
第四節 藥物控制釋放    13
1　藥物釋放模式    13
1.1　Zero order model    13
1.2　First order model    14
1.3　Higuchi model    14
2　Pickering emulsions    16
3　Cyclodextrin-based Pickering emulsions    18
第參章 研究目的    20
第肆章 材料與方法    22
第一節 實驗試劑與儀器設備    22
1　實驗試劑    22
2　儀器設備    24
第二節 實驗方法    26
1　BPC 溶解度測試    26
2　CD-MCT inclusion complex 鑑定    26
3　配方製備    26
3.1　Pickering emulsions 製備    26
3.2　Control solution (3% BPC) 製備    27
3.3　Control gel (3% BPC) 製備    27
3.4　Postive control (0.25% BPC-HCl) 製備    27
4　Pickering emulsions 粒徑量測    28
5　BPC 濃度分析    28
5.1　Pickering emulsions 配方分析前處理    29
5.2　Pickering emulsions 配方 HPLC 分析條件    29
6　傅立葉轉換紅外線光譜儀 (Fourier-transform infrared spectroscopy, FTIR)    29
7　光學顯微鏡    30
8　掃描式電子顯微鏡 (Scanning Electron Microscopy, SEM)    30
9　流變儀 (Rheometer)    30
9.1　Frequency sweep    30
9.2　Oscillatory stress sweep    31
10　In vitro 藥物釋放試驗    31
11　In vitro 皮膚滲透試驗    32
11.1　皮膚滲透藥物累積量    32
11.2　皮膚內藥物含量萃取    33
11.3　皮膚滲透試驗 HPLC 分析條件    33
12　共軛焦雷射掃描顯微鏡 (Confocal laser scanning microscope, CLSM)    33
13　動物皮膚刺激試驗    34
13.1　實驗方法    34
13.2　刺激性評分標準    34
13.3　藥物刺指數之計算與皮膚刺激性程度判定標準    35
14　In vivo 動物麻醉效果評估    36
14.1　實驗方法    36
14.2　實驗結果評估與定義    37
15　統計方法    37
第伍章 結果與討論    38
第一節 Pickering emulsions 的製備與物理化學性質之探討    38
1　實驗結果    38
1.1　BPC 在不同水溶液之溶解度    38
1.2　CD-MCT inclusion complex 結構鑑定    38
1.3　使用 BPC 與 MCT 製備 Pickering emulsions    39
1.4　BPC 濃度之影響    40
1.5　利用光學顯微鏡觀察 Pickering emulsions 巨觀結構    41
1.6　MCT 濃度之影響    42
1.7　CD 濃度之影響    42
1.8　藥物釋放試驗    43
2　綜合討論    44
第二節 油相結構對皮膚滲透效果之影響    47
1　實驗結果    47
1.1　BPC 在不同油相之溶解度    47
1.2　使用不同結構油相製備 Pickering emulsions    48
1.3　利用 SEM 觀察 Pickering emulsions 微觀結構    49
1.4　使用不同油相配方之藥物釋放試驗    50
1.5　使用不同油相配方之皮膚滲透試驗    51
1.6　將 BPC 溶於油相或經 Pickering emulsions 包覆之皮膚滲透試驗    53
1.7　利用 CLSM 探討皮膚滲透機制    54
1.8　動物皮膚刺激試驗    56
1.9　安定性試驗    56
2　綜合討論    57
第三節 油水界面之組成對流變特性之影響    63
1　實驗結果    63
1.1　添加 surfactants    63
1.2　添加 co-surfactants    64
1.3　提高 CD 濃度    65
1.4　流變特性的探討    66
1.5　不同表面特性配方之藥物釋放試驗    67
1.6　不同表面特性配方之皮膚滲透試驗    68
1.7　動物皮膚刺激試驗    69
1.8　安定性試驗    70
2　綜合討論    71
第四節 給藥頻率對麻醉效果之影響    75
1　實驗結果    75
1.1　混合不同油相    75
1.2　混合不同油相並添加 Cremophor ELP    76
1.3　混合不同油相並添加 Cremophor ELP 配方之藥物釋放試驗    77
1.4　混合不同油相配方之皮膚滲透試驗    78
1.5　混合油相並添加 Cremophor ELP 配方之皮膚滲透試驗    80
1.6　增加給藥劑量之皮膚滲透試驗    81
1.7　不同給藥頻率之皮膚滲透試驗    83
1.8　Pickering emulsions 之動物麻醉藥效評估    85
1.9　不同給藥頻率之動物麻醉藥效評估    87
2　綜合討論    89
第陸章 結論    98
第柒章 參考文獻    100
附錄 動物實驗申請書    105

                                

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