复方孕二烯酮周效避孕贴剂的体外经皮渗透及体内药代动力学

制备含孕二烯酮与炔雌醇的周效避孕贴剂,并对其体内外质量进行考察。分别建立孕二烯酮和炔雌醇体外含量测定的HPLC法,进行鼠皮渗透试验,并按照中国药典测定释放度;分别建立孕二烯酮和炔雌醇体内分析的LC-MS/MS和GC-MS法,研究贴剂家兔经皮给药的药代动力学行为。结果表明,孕二烯酮与炔雌醇的体外鼠皮渗透均呈零级动力学,渗透速率分别为0.377,0.092μg/(cm2.h);两种药物的体外释放均符合Higuchi方程,168 h累积释放百分率分别为90.7%和92.2%;复方孕二烯酮贴剂与市售片剂家兔给药后,孕二烯酮的cmax分别为(4.44±0.24),(8.43±2.15)ng/mL,tmax分别为(12.50±1.96),(0.20±0.05)h,AUC分别为(1 029.25±91.58),(311.84±100.88)ng/mL.h;炔雌醇cmax分别为(2.63±0.13),(7.85±1.73)ng/mL,tmax分别为(48.44±7.61),(0.25±0.02)h,AUC分别为(752.40±62.91),(216.10±56.83)ng/mL.h。两种药物的周效贴剂与市售片剂相比,cmax显著减小,tmax明显延长,AUC显著增大,具有显著或极显著性差异。复方孕二烯酮贴剂一次给药即能维持较长时间(7 d)平稳的血药浓度,有望成为新型的非口服避孕制剂。

In vitro permeation and in vivo pharmacokinetics of once-weekly contraceptive patch containing gestodene and ethinlyestradiol

The aim of this study was to prepare the once-weekly contraceptive patch containing gestodene(GSD) and ethinlyestradiol(EE) and to study its in vitro and in vivo characterization.A method for determination of GSD and EE in vitro by HPLC was established,and permeation tests were conducted in mouse skin.Release tests were conducted according to Chinese Pharmacopoeia.The plasma-concentrations of GSD and EE were determined by LC-MS/MS and GC-MS,respectively,so as to study the pharmacokinetic behavior of transdermal patches in rabbits.The in vitro transdermal permeation of both drugs from the patches displayed a zero-order process,permeation rate constants were 0.377 μg/(cm2 ·h) for GSD,and 0.092 μg/(cm2 ·h) for EE.The in vitro release profiles of both drugs were in accordance with Higuchi equation and the cumulative release percentages in 168 hours were 90.7% and 92.2%,respectively.After administration of compound GSD patches and commercial tablets in rabbits,cmax of GSD were(4.44±0.24) and(8.43±2.15) ng/mL;tmax were(12.50±1.96) and(0.20±0.05) h;AUC were(1 029.25±91.58) and(311.84±100.88) ng/mL ·h,respectively.cmax of EE were(2.63±0.13) and(7.85±1.73) ng/mL;tmax were(48.44±7.61) and(0.25±0.02) h;AUC were(752.40±62.91) and(216.10±56.83) ng/mL ·h,respectively.Compared with commercial tablets,cmax of patches of both drugs were reduced,while tmax were prolonged and AUC were enhanced.The results showed that the once-weekly contraceptive patch could maintain the drug release through rabbit skin for at least 7 days.The novel prepared patch might be a promising non-oral contraceptive preparation.