Terbinafine固態油相奈米粒子劑型之局部給藥系統開發研究

Development of Terbinafine Solid Lipid Nanoparticles for Topical Delivery System

張宗威(Tsung-Wei Chang)

指導教授 ： 許明照

臺北醫學大學/藥學院/藥學研究所/碩士(2011年)

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。

關鍵字

terbinafine ； solid lipid nanoparticles ； topical delivery system

並列摘要

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.

並列關鍵字

terbinafine ； 香港腳 ； 固態油相奈米粒子 ； 局部給藥系統

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