非洛地平-美托洛尔复方经皮给药系统的制备及其兔体内生物利用度

Preparation of transdermal drug delivery system of felodipine-metoprolol and its bioavailability in rabbits

制备了非洛地平-美托洛尔复方经皮给药系统,并研究其药剂学性质及经兔皮肤给药的药代动力学和生物利用度。先建立了同时测定贴剂和经皮渗透液中非洛地平与美托洛尔含量的RP-HPLC方法,以考察贴剂的药物体外稳态透皮速率和经皮渗透机制,并进行质量控制和评价;再以高灵敏度的GC-ECD方法分别测定非洛地平和美托洛尔的血药浓度,研究贴剂经皮给药后在兔体内的药代动力学和生物利用度。结果显示,该给药系统的复方药物体外透皮转运具有零级动力学特征,其含量均匀度检查符合2005版中国药典规定,稳定性好;经皮给药的血药浓度明显较口服平稳,且波动性小,达峰时间推后,持效时间延长,非洛地平与美托洛尔的相对生物利用度分别为275.37%和189.76%。以上结果表明,非洛地平-美托洛尔复方经皮给药系统具有明显缓释特征,可较长时间维持稳定有效的血药浓度。

To prepare transdermal drug delivery system （TDDS） of felodipine and metoprolol and to study its pharmaceutical characteristics, pharmacokinetics and bioavailability in rabbits, an HPLC assay was established for the simultaneous determination of felodipine and metoprolol in the permeation receptor and patch. The permeation rate and permeation mechanism of felodipine-metoprolol-TDDS through rabbit skin in vitro was examined. The determination of drug content, the examination of content uniformity and stability of the TDDS were carried out. GC-ECD assays were established for the determination of felodipine and metoprolol in plasma separately and then employed to study the pharmacokinetics and bioavailability of felodipine and metoprolol after a single dose of oral or transdermal administration in rabbits. The results indicated that the permeation of flodipine and metoprolol from the patch through excised rabbit skin exhibited zero-order kinetic characteristics. The determination of drug content and the quality control of content uniformity of the patch accorded with Pharmacopoeia of the People＇ s Republic of China of 2005 edition and the pharmaceutical characterization showed good stability. In contrast to oral delivery, relatively constant, sustained blood concentration with minimal fluctuation and prolonged peak time were observed over a long period after transdermal administration. The relative bioavailability of felodipine and metoprolol were 275.37% and 189.76% versus oral administration respectively. It was evident that the felodipine-metoprolol-TDDS exhibited good controlled release properties that satisfied the demands of original design that enhancing bioavailability and maintaining appropriate blood levels for a prolonged time without adverse effects associated with frequent oral administration.