Apomorphine微乳劑經皮傳遞系統之研究

Study of apomorphine-loaded microemulsions for transdermal drug delivery

陳易承(Yi-Cheng Chen)

指導教授 ： 吳寶珠

高雄醫學大學/藥學院/藥學研究所/碩士(2014年)

摘要

Apomorphine為D1和D2多巴胺受體類似劑，皮下注射apomorphine能大幅降低巴金森氏症之難治性的陣發性停電 (on-off phenomenon)。但因apomorphine半衰期短，故為維持其療效則需多次少量的皮下注射，而影響病人之順從性。此缺點擬用經皮輸送系統來改善，但apomorphine應用在經皮吸收的生體可用率低，所以本研究擬藉由微乳劑作為藥物載體，微乳劑是一種由油相、水相、界面活性劑和輔助界面活性劑所組成的劑型，在作為藥物輸送載體上有許多優點，如增加藥物溶解度、提升皮膚滲透度，進而改善生體可用率，使藥物經由皮膚持續吸收並維持一定的體內治療濃度，來減少多次給藥的不便性，進而提升病人的服藥順從性。經由本實驗室開發的微乳劑處方篩選出最佳穿透處方，但此處方的安定性不佳，本研究首先尋找最安定的處方，探討微乳劑水相中不同抗氧化劑vitamin C、sodium bisulfite對apomorphine的安定性影響。結果顯示，含有sodium bisulfite對藥物的安定性有很好的安定效果，在第六十天時，藥物殘餘量仍高於90%。而在體外穿透性試驗結果顯示微乳劑油相中之ascorbyl palmitate抗氧化劑對藥物穿透無影響。經由篩選過的抗氧化劑處方為水相含0.3% sodium bisulfite，IPM含0.05% ascorbyl palmitate，以此處方經皮給藥評估大鼠體內藥物動力學，在第15小時候達到穩定且持續觀察到48小時，1%與3%處方血中濃度分別為454.34 ng/mL與3137.66 ng/mL。藥效學以對側旋轉反應評估臨床皮下注射的APO-goR Pen (apomorphine solution) 0.5 mg/kg (平均轉圈速率6.92次/分) 與經皮給藥處方1%與3% (2.17次/分、5.55次/分)，得知apomorphine微乳劑處方在體內穩定釋出，且能延長藥物作用時間。

關鍵字

Apomorphine ； 經皮吸收 ； 微乳劑 ； 帕金森氏症

並列摘要

Apomorphine is a potent D1 and D2 dopamine receptor agonist, which is effective in the treatment of Parkinsonism. Unfortunately, the short duration of apomorphine needs high injection frequencies. It can be improved by transdermal system delivery. According to the previous study, apomorphine transdermal delivery only showed low bioavailability. Microemulsion which compose of oil phase, aqueous phase, surfactant and cosurfactant provided several advantages for transdermal drug delivery, such as increased drug solubility, enhanced skin penetration, and improved the bioavailability, as well as easy to prepare. Hence, miceoemulsion was used as carrier in this study. We choosed the formulation which had the most cumulative amount from previous studies, but the formulation was not stable. First, the study explored the effect of different antioxidant (vitamin C and sodium bisulfite) in water phase. The results showed that the stability of drugs containing sodium bisulfite was stable, and drug content was higher than 90% after 60 days. In vitro skin permeation experiment showed that antioxidant ascorbyl palmitate of oil phase didn’t influence skin permeation. The formulation containing 0.3% sodium bisulfite in aqueoce phase and 0.05% ascorbyl palmitate in oil phse showed more stable, and then the pharmacokinetics and pharmacodynamic studies were performed. After 15 hours, the plasma concentration achieved steady state. The plasma concentrations of formulations containing 1% and 3% drug were 454.34 ng/mL and 3137.66 ng/mL in the first 48 hours. The mean contralateral rotation rate of subcutaneous APO-goR Pen (apomorphine solution) 0.5 mg/kg was 6.92 count/min. The 1% and 3% formulation were 2.17 count/min and 5.55 count/min. Apomorphine-loaded microemulsions for transdermal drug delivery could release stably in vivo and extend the duration of drug action.

並列關鍵字

Apomorphine ； Transdermal drug delivery ； Microemulsions ； Parkinson’s disease

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