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系統識別號 U0007-2807201116202500
論文名稱(中文) Terbinafine固態油相奈米粒子劑型之局部給藥系統開發研究
論文名稱(英文) Development of Terbinafine Solid Lipid Nanoparticles for Topical Delivery System
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 張宗威
研究生(英文) Tsung-Wei Chang
學號 M301098035
學位類別 碩士
語文別 中文
口試日期 2011-07-19
論文頁數 90頁
口試委員 委員-林山陽
委員-蔡義弘
委員-林文貞
委員-何秀娥
指導教授-許明照
中文關鍵字 terbinafine  solid lipid nanoparticles  topical delivery system 
英文關鍵字 terbinafine  香港腳  固態油相奈米粒子  局部給藥系統 
學科別分類
中文摘要 Terbinafine是一種抗黴菌藥物,臨床上常用於香港腳局部治療。目前市面上治療香港腳製劑面臨到給藥時間長和頻次多的問題,本研究藉由固態油相奈米粒子(solid lipid nanoparticles)劑型中可承載疏水性藥物和粒徑小的特性,來開發給藥時間短和頻次少的處方。處方以微乳劑形成法(microemulsions technique)來製備固態油相奈米粒子,其中固態油相選用Glyceryl Monostearate(GMS)、Glyceryl Behenate(Compritol 888)和Glyceryl Palmitostearate(Precirol ATO 5),界面活性劑選用Tween和Cremophor系列來建立三相圖找出能維持澄清的處方組成。體外穿皮試驗中以裸鼠皮作為給藥模式,市售產品Lamisil® Once作為對照組,比較各處方在投予24小時後角質層、表皮層和真皮層中藥物濃度的差異。透過粒徑分析儀來觀察處方製備後粒徑大小的變化,各處方製備後粒徑大小多介於80~200nm之間,其中以CPa和ATOb處方安定性較佳,製備完成後28天依然維持澄清,測得平均粒徑大小分別為243.3nm和197.6nm。體外穿皮試驗中以ACP1-GM1處方與Lamisil® Once在角質層和表皮層的藥物濃度最接近,而真皮層藥物濃度在給藥12小時後已相當接近Lamisil® Once給藥24小時;給藥24小時後,真皮層藥物濃度更是Lamisil® Once的1.17倍。本研究將Terbinafine HCl結合到固態油相奈米粒子劑型上,發現處方中固態油相可包埋溶解度差的Terbinafine HCl以奈米粒子穿透皮膚,增加Terbinafine HCl進入皮膚的濃度,因此可減少給藥時間與頻次。最後,縱使固態油相奈米粒子安定性不佳仍需改進,但在香港腳局部治療還是非常具有發展潛力。
英文摘要 Terbinafine is an antifungal agent which is topically used on athlete's foot clinically. The problems of commercial products are long treatment duration and high dosing frequency. Our study develops the formula with short treatment duration and less dosing frequency that is based on two characteristics of solid lipid nanoparticles(SLNs) which has ability to load the lipophilic drug and smaller particle size. The SLNs is manufactured by microemulsions technique which is used Glyceryl Monostearate(GMS), Glyceryl Behenate(Compritol 888) and Glyceryl Palmitostearate(Precirol ATO 5) as the solid lipid phase and the Tween series and Cremophor series as the surfactant to construct ternary phase diagram to find the transparent formula. In vitro transdermal experiment used the nude mice as a model and the commercial product “Lamisil® Once” as a reference to compare the amount of terbinafine HCl in the stratum corneum, viable epidermis and dermis with each formula after 24 hours administration. Using particle size analyzer detecting the particle size of formulae are around 80 to 200 nm. Formula CPa and ATOb have better stability and maintained transparent solution after 28 days of manufacture with the mean particle size 243.3 nm and 197.6 nm, respectively. Formula ACP1-GM1 has the closest amount of terbinafine HCl in stratum corneum and viable epidermis compared with Lamisil® Once. After treating with ACP1-GM1 12 hours later, the amount of terbinafine HCl in dermis is much closer to the Lamisil® Once which is treated after 24 hours and has no statistically significant difference. Exhilaratingly, the amount of terbinafine HCl in dermis at 24 hours on ACP1-GM1 group was 1.17 times higher than that on Lamisil® Once. To combine with terbinafine HCl and SLNs discovered the solid lipid phase could embed poor solubility drug with nano size to penetrate through the skin. Not only could increase the amount of terbinafine HCl in the skin, but also could reduce treatment duration and frequency. Last but not least, even though the SLNs formula is unstable, it has great potential for athlete’s foot topical treatment.
論文目次 目錄 ...........I
附圖目錄 ...........IV
附表目錄 ...........VIII
中文摘要 ...........X
Abstract ...........XII
壹、緒論 ...........1
第一節、研究背景介紹 ........1
一、皮膚構造與皮膚黴菌感染 ........1
二、香港腳的治療與現今製劑 ........7
三、影響Terbinafine局部給藥系統作用之因子 .......13
四、固態油相奈米粒子(Solid lipid nanoparticles)劑型簡介 ........16
第二節、研究目的 ........22
貳、實驗材料與方法........23
第一節、實驗材料 ........23
第二節、儀器設備 ........24
第三節、實驗方法 ........25
一、Terbinafine Hydrochloride分析方法........25
二、溶解度試驗 ........26
三、固態油相奈米粒子(SLN)處方製備........27
四、粒徑分析 .........29
五、掃描式電子顯微鏡(Scanning Electron Microscope).......31
六、體外穿皮試驗 .......31
七、數據統計分析 .......34
參、結果與討論 .......35
第一節、實驗方法之確效 .......35
一、Terbinafine HCl分析方法確效 ......35
二、萃取方法確效 ......38
三、Tape-stripping次數確效 ........39
第二節、溶解度試驗 ......45
一、固態油溶解度 ......45
二、賦形劑溶解度 ......46
第三節、SLN三相圖建立 .......48
第四節、體外穿皮試驗及處方優化 .......57
一、市售產品Lamisil® Once ......57
二、基礎處方 .......58
三、水相中加入酒精或角質溶解劑 .......60
四、增加處方油相比例 .......64
五、混合兩種不同固態油 .......66
第五節、粒徑分析 ........82
肆、結論 ........85
伍、參考文獻 .......87

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