離子液體於層析靜相製備及有機金屬骨架材料於藥物釋放之應用

Ionic Liquids for Chromatographic Column Preparation and Metal-Organic Framework for Drug Delivery

布蘭達(Brenda Singco)

指導教授 ： 黃悉雅

中原大學/理學院/化學研究所/博士(2013年)

https://doi.org/10.6840/cycu201300164

摘要

摘要
本論文主題分為兩部分進行探討。首先證明以有機金屬骨架(metal-organic framework, MOF, MIL-100(Fe))為載體，進行阿斯匹靈(aspirin)的藥物釋放的可能性，接著則是探討以離子液體(ionic liquid, IL)製備孔洞性層析靜相之影響。
在第一部分中，我們成功的以沉浸方式將MOF浸泡至飽和阿斯匹靈溶液中24小時，將阿斯匹靈於負載於MIL-100(Fe)中。本研究利用量測MOF的表面積與孔洞體積變化量來探討其藥物乘載及釋放特性，並且以質譜的檢測進行藥物負載量之鑑定。結果證明，當阿斯匹靈負載於MOF時，其表面積及孔洞體積將各別減少36 %與32 %。質譜結果顯示每1 mg MOF可負載約1806-1962 μg 的阿斯匹靈藥物。
我們同時在磷酸鹽緩衝溶液(pH 7.4)及0.1 M鹽酸溶液(pH 1.2)條件下以持續釋放法(sustained release formulation)檢測MIL-100(Fe)之釋放曲線，其釋放時間為8小時。此外，我們也同時評估並比較以不同配位基(trimesic acid)合成MIL-100(Fe)對藥物釋放之差異。
於第二部分中，我們提出以離子液體結合微波輔助加熱方式快速製備一系列不同烷基鏈長(C4-C18)的methacrylate- based整體成形靜相，並將其運用於層析方法中。本實驗首先以一系列不同陽離子碳鏈長度(C4-C10)與不同陰離子種類([BF4]-, [PF6]-及[Tf2N]-)的imidazolium-based 離子液體做為微波輔助反應的基質進行methacrylate-based層析靜相的聚合。探討離子液體種類對其孔洞性質之影響並對層析靜相條件進行最佳化。結果顯示，靜相之孔洞大小會隨著離子液體之碳鏈長度及陰離子疏水性增加而減小。此外，實驗中也發現在反應過程中結合兩種離子液體可有效提昇層析分離的效果。分別將此靜相用於毛細管電層析分離四種paraben，其滯留時間與波峰面積再現性之RSD皆小於5%。並且可運用於nano-LC系統中分離蛋白質水解胜肽。結果證明，以離子液體結合微波輔助加熱法製備高分子靜相可達到快速製備，綠色(無需有機溶劑)及節能的目標。

關鍵字

藥物釋放 ； 離子液體 ； 有機金屬骨架

並列摘要

Abstract
This study comprises two parts. The first part demonstrates the use of MIL-100(Fe) metal-organic framework (MOF) for the delivery of aspirin (acetylsalicylic acid) and the second part studies the influence of ionic liquids as pore formers in the fabrication of stationary phases for chromatography.
MIL-100(Fe) successfully encapsulated aspirin via a 24h immersion in a solution saturated with the drug. Quantification showed that 1806 – 1962 g of aspirin was loaded in 1 mg of MOF based from the TOF/MS measurement. Characterizations revealed that the decrease in the surface area and pore volume were 36% and 32%, respectively in the drug-loaded MIL-100(Fe) with respect to the empty MIL-100(Fe). Release profiles of aspirin-loaded MOF discs in both dissolution media, phosphate buffered saline (pH 7.4) and 0.1M HCl (pH 1.2), characterize a sustained release formulation. In addition, the construction of MIL-100(Fe) was modified by the incorporation of aspirin as one of the linkers (trimesic acid was the main linker) and the release of the material was also evaluated. The release profiles in both pHs showed sustainability for about 8 hours.
The second part of this two-part study demonstrates a green synthetic procedure using ionic liquids (ILs) in conjunction with microwave in the fabrication of methacrylate-based stationary phases for chromatographic application. Several imidazolium-based ILs with varying cation alkyl chain length (C4-C10) and anion type ([BF4]ˉ, [PF6]ˉ and [Tf2N]ˉ) were used as reaction media in the microwave polymerization of methacrylate-based stationary phases. Porous properties of the produced monoliths decreased when cation alkyl chain length and anion hydrophobicity was increased. Performance of these monoliths was assessed for their ability to separate structurally-related parabens by capillary electrochromatography (CEC). Relative standard deviations (RSD) of less than 5% for both retention time and peak area reproducibility exemplify monolith performance reliability for poly(BMA-EDMA-[C6mim][BF4]). This monolith was tested for its potential in nanoLC to separate protein digests. ILs as porogen also fabricated different alkyl methacrylate (AMA) (C4 to C18) monoliths. Furthermore, the use of binary IL mixtures improved chromatographic separation. The combination of ILs and microwave irradiation made polymer synthesis very fast (~10 min), entirely green (organic solvent-free) and energy saving process.

並列關鍵字

drug delivery ； Ionic liquids ； Metal-organic framework

參考文獻

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