The percutaneous absorption of 17B-Estradiol liquid formulation

• Main Authors: Tsai, Chia-Ling, 蔡佳伶
• Other Authors: Tsai Yi-Hung
• Format: Others
• Language: zh-TW
• Published: 1997
• Online Access: http://ndltd.ncl.edu.tw/handle/99449494701544420226

碩士 === 高雄醫學院 === 藥學研究所 === 85 === 17β-estradiol長久以來皆是用來當做雌性素補充治療的藥物，所使用 的劑型有口服、皮下注射、植入，或穿皮劑型。而在穿皮製劑與口服製劑 之比較上，口服製劑會因經過肝臟的首渡代謝效應而降低藥效，但穿皮製 劑卻不易受到首渡代謝效應的影響。穿皮劑型可製成軟膏 (ointment)、 凝膠 (gel) 和貼片 (patch) 等，但軟膏和凝膠常會沾到衣服或不小心擦 掉、洗掉，而貼片常會造成使用部位的過敏或發癢等不適，使病人在使用 上的順服力不高，為了改善這些缺點，本實驗將其製成單一劑量液劑來評 估17β-estradiol經皮吸收的效果。由於17β-estradiol為親脂性藥物， 對一般的水溶液幾乎不溶，所以藉由加入乙醇來增加藥物的溶解度和穿透 。然而，皮膚的角質層是影響藥物穿透的主要障壁，經皮吸收促進劑是最 常用於改善藥物對皮膚穿透的方法，所以為了促進17β-estradiol的穿透 ，本實驗以兔腹皮為穿透障壁，並加入PG、PEG 400、glycerine、azone 、terpenes類物質來當作經皮吸收促進劑。結果顯示propylene glycol (PG)、polyethylene glycol 400 (PEG 400) 和glycerine對促進17β- estradiol的穿皮效果並不好，反而妨礙17β-estradiol的穿透，所以不 適合當做17β-estradiol的促進劑。而azone的促進效果不錯，但是添加 量達0.5 %以後則是隨著添加的比例增加，穿透速率反而下降。Terpenes 類物質最常被拿來當經皮吸收促進劑，在本實驗所使用的terpenes中以 dl-limonene，d-limonene和1,8-cineol的促進效果最好，因此使用篩選 出來對17β-estradiol穿皮吸收效果較好的三種促進劑 (menthol, azone, 1,8-cineol) 製備單一劑量液劑並評估其揮發性及經皮吸收效果 ，結果發現，含2.5 % menthol的單一劑量液劑揮發最慢，而含4.5 % 1,8-cineol之處方三的藥物累積量和flux為最高，表示其穿透效果最好； 在投與次數方面，以一天投與2次的藥物累積量最高，這表示補充越多 的17β-estradiol量，所以使藥物累積量提高，而且在開放系統之下， lag time幾乎小於1小時，表示投與之後能迅速促使17β-estradiol穿透 兔腹皮。而另一個實驗是以人皮為穿透障壁，觀察市售品Oestrogel和自 製液劑處方，發現液劑處方三的穿透效果最好。所以在將來的發展上，可 以朝單一劑量液劑這方面來改善和研究 17β-estradiol was used to be estrogen replacement therapeutic drug for a long time. Its dosage forms included oral, subcutaneous injection, implants, or transdermal route. The side effects of transdermal route were not like oral route that would have first pass effect in the liver and reduce the effect of drug. The dosage forms of transdermal estradiol included ointment, gel and patch. In this study, a new dosage formiquid formulation was developed to estimate the effect of transdermal absorption of estradiol.Because 17β-estradiol is a lipophilic drug, it is almost insoluble in the aqueous solution. So, adding ethanol is a good way to increase the solubility of drug and to promote the penetration, and ethanol could be the component of estradiol liquid formulation. However, stratum corneum of skin was potential rate-determining barrier. It limited the penetration of drug. In order to increase the penetration of estradiol through the stratum corneumof the rabbit abdominal skins, PG, PEG 400, glycerine, azone and terpenes were used to be transdermal absorption enhancers in this study.The results showed that PG, PEG 400, and glycerine were poor effect of penetration for estradiol. They had a retarding effect for estradiol. So, they were not suitble to add to the formulation. Azone had good penetration effect, but its penetration capacity of estradiol decreased following increase of azone concentration. Terpenes were usually used to be penetration enhancers. In this study, dl-limonene and d-limonene had the best effect of penetration to estradiol, especially 1% d- limonene. So, adding d-limonene to the estradiol liquid formulation may be useful for the transdermal absorption of estradiol through the barrier of the stratum corneum. The liquid formulation can be developed to modify the deficiecy of other transdermal route. In the liquid formulations, menthol, azone and 1,8-cineol were used to be penetration enhancers. In open condition, the volatile rate, flux and accumulative amount of estradiol in different administration intervals were estimated and investigated in this study. The results showed that the volatile rate of the liquid formulation 1 included 2.5 % menthol was slower than others. The accumulative amount and flux of the liquid formulation 3 included 4.5 % 1,8-cineol was greater than others, it mean that the penetrating effect of liquid formulation 3 was the best. In the part of administration intervals, the results showed that in the experiment administrating twice a day, the accumulative amount was much more than others. The open condition would shorten the lag time and improve 17β-estradiol to penetrate through the skins. In another experiment, human skins were penetrating barrier. Oestrogel was compared with liquid formulation 1 and 3. The result showed that the accumulative amount of liquid formulation 3 was greater than others. In the future, the development of this system can be modified and investigated