美洛西卡凝膠經皮吸收研究

Study on the Transdermal Delivery of Meloxicam Gel

張瑞昇(Jui-Sheng Chang)

指導教授 ： 蔡義弘

高雄醫學大學/藥學院/藥學研究所/博士(2008年)

https://doi.org/10.6832/KMU.2008.00158

摘要

Meloxicam (C14H13N3O4S2) 是一種非固醇類抗發炎藥物，主要用於治療風濕性關節炎、骨關節炎和退化性關節病等疾病。雖然Meloxicam是對於抑制cyclooxgenase-2較有選擇性之藥物，但仍有部份的抑制cyclooxgenase-1作用，所以仍有部分的腸胃之副作用；因此為了避免胃腸道副作用，研發meloxicam經皮輸藥系統，而對於meloxicam的特性來說，口服劑量小、低分子量、高脂溶性與良好的組織耐受性可作為經皮輸藥劑型潛力。在這項研究，混合溶媒系統和不同的類型經皮促進劑用於提高藥物穿透透率和減少延遲時間。為了迅速地獲得合適化處方，利用電腦合適化技術運用多項等式的效應曲面法(RSM)，用來搜尋meloxicam合適化處方和有效地定量多項式變數對藥物穿透的影響性。利用uniform design設計合適化處方，將促進劑azone (x1)、sodium lauryl sulfate (x2)、and menthol (x3)當作因子，結果顯示azone對藥物經皮吸收是最有影響效果；使用效應曲面法來獲得pH 7.4緩衝液與乙醇之混合溶媒系統以便製備meloxicam hydrogel，其混合溶媒系統具有協同作用，可以增加藥物的溶解度，最高的溶解度混合溶媒為pH 7.4 緩衝液與乙醇比例為50:50。Terpenes類促進藥物吸收被評估於體內與體外研究，一系列terpenes當作促進劑改善meloxicam穿透速率，其有效增加穿透速率70-539倍，延遲時間則縮短7.92到0.17小時，terpenes當中最有作用的是menthol；因此效應曲面法可用來獲得合適的混合溶媒系統及設計meloxicam凝膠。

關鍵字

Meloxicam ； 效應曲面法 ； 經皮輸藥系統

並列摘要

Meloxicam is a potent, newer nonsteroidal anti-inflammatory drug and used in treatment of reheumatoid arthritis, osteoarthritis and degenerative joint disease. Although meloxicam preferentially inhibits cyclooxgenease-2 over cyclooxgenease-1, it still has parts of incidence of gastrointestinal side effect. In order to reducing side effect of meloxicam, we developed the transdermal delivery system. In view of the characteristics of meloxicam including small
oral dose, low molecular weight, higher lipid solubility and excellent tissue tolerability, it seems that there is potential for investigating the meloxicam transdermal dosage as an additional route for meloxicam administration. In this study, the mixed-solvent and different types of penetration enhancers were used to enhance the penetration rate and decrease the lag time. In order to speedily obtain the optimal formulation, a computer optimization technique, based on a response surface methodology (RSM) utilizing polynomial equation was used to search for the optimal meloxicam formulation and efficiently quantify the influences of formulation variables on the drug permeation. The uniform design was applicable to prepare systematic model formulations which were composed of three formulation factors: the content of azone (x1), sodium lauryl sulfate (x2), and menthol (x3). The result showed that azone had the most potential influence on the percutaneous absorption of meloxicam. The response surface methodology was used to obtain an appropriate mixed-solvent system of pH-7.4 buffer and ethanol for preparing meloxicam hydrogel. The mixed-solvent system of pH-7.4 buffer and ethanol had a synergistic effect on the increase of drug solubility. The highest solubility was obtained in the ratio of 50/50 pH 7.4 buffer/ethanol. The enhancement effects of terpenes on drug precautious absorption were evaluated via in vitro and in vivo study. A series of terpenes were used as enhancer for improving the penetration rate of meloxicam. The penetration rates were significantly increased by about 70–593 fold and the lag times were shortened from 7.92 to 0.17 hr by enhancer incorporation. Among these terpenes, menthol showed the greatest effect. The result showed that the response surface methodology and multiple response optimization utilizing a polynomial equation can be successfully used to obtain the optimal mixed-solvent system and design a meloxicam hydrogel.

並列關鍵字

Meloxicam ； response surface methodology ； transdermal delivery system

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