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目的观察黄体酮乳膏剂经皮给药在大鼠体内的药动学参数和生物利用度变化,为其临床应用提供依据。方法选择健康无卵巢的Wistar大鼠6只,随机分为口服组和经皮组,每组3只。两组均行双周期双交叉试验:分别单次给予黄体酮胶囊(灌胃)、黄体酮乳膏剂(贴覆)各50 mg/kg。口服组用药前,用药后0、5、10、20、30 min及1、2、4、6、8、10、12、24、48、72 h眼眶取血0.4 m L;经皮组用药前,用药后0、0.5、2、4、8、16、24、32、40、48、56、64、72h眼眶取血0.4 m L。末次取血后停药至少2周,两组交叉给药,同首次给药途径相同时间再次取血。采用ELISA法检测黄体酮血药浓度,DAS药动学软件对数据进行处理,比较两种剂型的药动学参数及生物利用度。结果经皮组、口服组AUC0~72 h分别为(1 131.43±369.10)、(161.44±94.63)μg/L×h,AUC0~∞分别为(2 364.05±289.25)、(180.90±12.78)μg/L×h,tmax分别为(14.67±3.87)、(1.12±0.31)h,Cmax分别为(49.92±8.41)、(33.56±15.68)μg/L,t1/2ke分别为(63.11±114.81)、(18.71±8.18)h,二者比较P均<0.05。黄体酮乳膏剂的生物利用度是黄体酮胶囊的353.7%。结论黄体酮乳膏剂经皮给药具有明显的长效、缓释特征,有望成为安全、长效且使用方便的制剂。
Objective To observe the changes of pharmacokinetic parameters and bioavailability of progesterone creams transdermally in rats and provide the basis for its clinical application. Methods Six healthy Wistar rats without ovary were randomly divided into oral group and transdermal group, with 3 rats in each group. Double-cycle double-crossover test was performed in both groups: a single dose of progesterone capsules (intragastrically) and a 50 mg / kg dose of progesterone cream (paste) were given respectively. Oral group before treatment, 0,5,10,20,30 min after treatment and 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 h orbital blood 0.4 m L; , After treatment 0,0.5,2,4,8,16,24,32,40,48,56,64,72h orbital blood 0.4 m L. After the last blood withdrawal for at least 2 weeks, two groups of cross-administration, the same time as the first route of administration to take blood again. The serum concentration of progesterone was detected by ELISA and the data were processed by DAS pharmacokinetics software. The pharmacokinetic parameters and bioavailability of the two formulations were compared. Results AUC0 ~ 72 h were (1 131.43 ± 369.10) and (161.44 ± 94.63) μg / L × h, respectively, and AUC0 ~ ∞ were (2 364.05 ± 289.25) and (180.90 ± 12.78) μg / L × h and tmax were (14.67 ± 3.87) and (1.12 ± 0.31) h respectively, and the C max values were (49.92 ± 8.41) and (33.56 ± 15.68) μg / L and t1 / 2ke were 63.11 ± 114.81 and 18.71 ± 8.18) h, both P <0.05. The bioavailability of progesterone cream is 353.7% of progesterone capsules. Conclusions Progesterone creams have obvious long-term and sustained-release characteristics and are expected to become safe, long-lasting and easy-to-use preparations.