chondroitin sulfate高分子前驅藥之合成與性質探討

Synthesis and characterization of chondroitin sulfate macromolecular prodrug

林世昌(Shih-Chang Lin)

指導教授 ： 王麗芳

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/碩士(2005年)

摘要

Ibuprofen、ketoprofen和naproxen為非含類固醇的抗發炎藥(non-steroidal anti-inflammatory drugs, NSAIDs) 被廣泛用在控制風濕病所引起的發炎與疼痛，而chondroitin sulfate多醣体為S/DMOAD (structure/ disease modifying anti-osteroarthritis drug)之翹楚，並具結腸標的之功能。若能將NSAID與Chondroitin sulfate結成一体，對於抗發炎作用將會有增強效果並且也解決長期使用NSAID藥物後引起腸胃潰瘍之副作用問題。本研究利用N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDAC) 為縮合劑，將模型藥ibuprofen、ketoprofen和naproxen以polyethylene glycol (PEG) 為隔離基 (spacer) 接枝到Chondroitin sulfate鏈上，控制反應條件將可合成一系列不同藥物取代程度之高分子前驅藥，以HPLC分析此類前驅藥在pH 7.4緩衝溶液下之藥物水解動力學，並探討在酯水解酶 (esterase) 和硫酸化軟骨素水解酶 (chondroitinase) 存在下對前驅藥的水解催化作用，期望此高分子前驅藥能達到延遲藥物釋放及結腸標的效果。

關鍵字

非含類固醇抗發炎藥 ； 結腸標的 ； 硫酸化軟骨素

並列摘要

Ibuprofen, ketoprofen and naproxen are non-steroidal anti- inflammatory drugs (NSAIDs) for controlling pain and inflammation in rheumatic diseases. Their main disadvantage is a relatively short plasma half-life, which results in a short activity duration and pronounced ulcerogenic potency. In order to overcome these problems, the potentially colon-specific chondroitin sulfate (ChS, one of the common-used S/DMOAD) will be linked with ibuprofen, ketoprofen and naproxen using PEG as a spacer. The PEG-drug adducts will be synthesized using 1,1’-carbonyldiimidazole as a coupling reagent followed by the reaction with chondroitin sulfate in dilute concentration via N-ethyl-N”-(3-dimethyl-aminopropyl) -carbodiimide hydrochloride (EDAC) as a conjugated agent. The various degrees of drug substitution on ChS will be characterized and their enzymatic cleavage by chondroitinase will be studied by GPC. Moreover, the free drugs released from these drug-linked ChS will be evaluated in the presence of esterase, chondroitinase or both by HPLC.

並列關鍵字

colon-specific ； NSAIDs ； chondroitin sulfate

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