DEXAMETHASONE聚合膠體劑型於經皮輸藥系統之研究

Study of dexamethasone transdermal delivery by polymer gels

黃思瑜(SZU-YU HUANG)

指導教授 ： 廖嘉鴻

臺北醫學大學/藥學院/藥學系(碩博士班)/碩士(2013年)

摘要

本研究目的將臨床上具抗發炎和免疫作用的皮質類固醇–迪皮質醇(Dexamethasone, DEX)作為經皮投予的藥物研究，利用高分子聚合物 ( polymer )以物理性混合方式製備迪皮質醇穿皮製劑的膠體。聚合物利用測定臨界膠質體濃度、凝膠濃度、迪皮質醇在聚合物之溶解度、粒徑大小、表面電位與釋放速率進行評估物化特性。皮膚穿透實驗方面，選用雄性裸鼠作為實驗動物，進行 (1)裸鼠之腹部皮膚進行迪皮質醇水溶液或含迪皮質醇(Dexamethasone, DEX)或加入薄荷醇(menthol)的聚合物體外穿透實驗。(2)評估含迪皮質醇(Dexamethasone, DEX)的聚合膠體或貼片在裸鼠體內的初步藥物動力學。結果顯示，聚合物的臨界膠質體濃度為0.5% (w/v)，並在32℃下高濃度的聚合物會形成凝膠態。而迪皮質醇(Dexamethasone, DEX) 聚合膠體在4℃下溶解度由62.17±2.99 µg/ml增至320.38±18.25 µg/ml；粒子大小和zeta電位分別為1.62±0.07 µm、0.09±0.20 mV；迪皮質醇水溶液和迪皮質醇聚合膠體的體外藥物釋放速率由15.2±0.69×10-2 µg cm-2√h-1降至2.5±0.1×10-2 µg cm-2√h-1。體外動物穿皮實驗中，迪皮質醇(Dexamethasone, DEX)水溶液的擬穿透係數在LC/MS/MS和HPLC分別為8.72±4.17 × 10-8 cm/s和1.59±0.33 × 10-8 cm/s；而含迪皮質醇(Dexamethasone, DEX) 聚合膠體的擬穿透係數在LC/MS/MS和HPLC分析下分別為4.09±2.13 × 10-9 cm/s和1.46±0.23 × 10-9 cm/s。在加入促進劑薄荷醇(menthol)後，迪皮質醇(Dexamethasone, DEX)水溶液和含迪皮質醇(Dexamethasone, DEX) 聚合膠體的擬穿透係數在HPLC分別為3.38±0.95 × 10-8 cm/s和3.18±0.92 × 10-9 cm/s，皆明顯比未加促進劑的高。初步體內藥物動力學實驗中，迪皮質醇(Dexamethasone, DEX) 聚合膠體直接塗抹膝關節12小時後，血中、關節液中的濃度在LC/MS/MS分析下分別為2.05±0.75ng/ml 和 0.47±0.12ng/ml。另外評估有添加或無添加薄荷醇之迪皮質醇聚合膠體的貼片(5cm2)，12小時後在HPLC分析下分別為9.32±1.19ng/ml和16.90±2.90ng/ml；48小時後在HPLC分析下則分別為21.39±2.54ng/ml和32.38±0.50ng/ml，顯示了以貼片形式給予的血中濃度顯著高於直接塗抹凝膠，且有添加薄荷醇的血中濃度在48小時後比未添加薄荷醇的提升了1.5倍。總結，高濃度的聚合物適合做為經皮傳遞的載體，且添加薄荷醇確實能提升迪皮質醇(Dexamethasone, DEX)的經皮通透量。

關鍵字

迪皮質醇；經皮傳遞；聚合膠體

並列摘要

The purpose of this study was used of non-invasive transdermal delivery of Dexamethasone (DEX), a glucocorticoid, used clinically as an anti-inflammatory and immunosuppressive agent to investigate feasibility of polymer gels as a release vehicle in vitro and in vivo. Critical micelle concentration, gelation concentration, solubility, size and zeta potential and release rate was evaluated for DEX/polymer. In nude mice skin permeation studies, (1) In vitro permeations of DEX/H2O and DEX/ polymer or add menthol were evaluated on abdominal skin of male nude mice. (2)The preliminary pharmacokinetic behavior of DEX with polymer gel or patch were studied in nude mice with transdermal administration. The results showed that the critical micelle concentration of polymer value was 0.5%. The polymer can forms gel with high concentration at 32℃. The solubility of DEX was observed increasing from 62.19±2.99µg/ml (DEX/H2O) to 320.38±18.25µg/ml (DEX/ polymer) under 4℃ condition. Size and ζ-potential of formulation (DEX/ polymer gels) was found 1.62±0.07µm and 0.09±0.20mv, respectively. The release rate of dexamethasone was found decreased from (PH2O) =15.2±0.69×10-2 µg cm-2√h-1 to (P polymer gels) =2.5±0.1×10-2 µg cm-2√h-1. The effect of polymer gels on mice skin also showed decrease in the apparent permeability coefficient from (PH2O) = 8.72±4.17×10-8 cm s-1 to (P polymer gels) = 4.09±2.13×10-9 cm s-1 and from (PH2O) = 1.59±0.33 ×10-8 cm s-1 to (P polymer gels) = 1.46±0.23×10-9 cm s-1 by LC/MS/MS and HPLC, respectively. In addition, the formulation (DEX/H2O or DEX/ polymer gels) with menthol were showed significant increase in the apparent permeability coefficient from (Pmenthol) = 3.38±0.95×10-8 cm s-1 to (P polymer gels with menthol) = 3.18±0.92×10-9 cm s-1 by HPLC. After transdermal administration of formulation (DEX/ polymer gels) 12hr on the joint, we found in the plasma and joint concentration was showed 2.05±0.75ng/ml and 0.47±0.12ng/ml by LC/MS/MS, respectively. After transdermal administration of DEX patch 12hr and 48hr on nude mice, we found in plasma concentration was 9.32±1.19ng/ml and 21.39±2.54ng/ml, respectively. In addition, the patch with menthol after 48hr was significant increase 1.5 folds in plasma concentration. Summary, polymer is a suitable vehicle for transdermal delivery and menthol is a useful as enhancer for the transdermal absorption of DEX.

並列關鍵字

dexamethasone；transdermal delivery；polymer gels

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