比较氨氯地平和阿托伐他汀复方片与单剂在健康人体的生物等效性

目的 评价氨氯地平/阿托伐他汀复方片剂与同剂量单剂的生物等效性.方法 66位健康男性志愿者随机交叉单次口服1片氨氯地平(5 mg)/阿托伐他汀(40 mg)复方片剂(受试制剂)和同时服用氨氯地平(5 mg)和阿托伐他汀(40mg)各1片(参比制剂);用GC-ECD法和LC-MS/MS法,分别测定药物血浆浓度,WinNonlin非房室模型计算药代动力学参数,SAS程序评价生物等效性.结果 受试制剂(复方)和参比制剂(单剂)的主要药代动力学参数,氨氯地平:tmax分别为6.0和6.0 h;t1/2分别为(39.2±7.6)和(39.7±9.9)h;Cmax分别为(3.0±0.9)和(3.0±0.5)ng·mL-1;AUC0-∞分别为(145.3±42.1)和(149.8±43.6)ng·h·mL-1;AUC0-t分别为(129.3±39.5)和(133.4±37.2)ng·h·mL-1.阿托伐他汀:tmax分别为1.0和0.5 h;t1/2分别为(6.7±1.8)和(6.9±1.8)h;Cmax分别为(18.8±9.8)和(20.2±11.7)ng·mL-1;AUC0-∞分别为(101.7±35.2)和(97.8±39.2)ng·h·mL-1;AuC0-t分别为(96.7±35.0)和(93.1±39.1)ng·h·mL-1.受试制剂和参比制剂AUC0-t、AUC0-∞和Cmax比值的90%置信区间:氨氯地平:93.3%～100.1%,93.8%～100.6%和95.8%～103.4%;阿托伐他汀:99.2%～111.0%,99.6%～110.6%和81.8%～107.2%.结论 2种制剂为生物等效制剂.     

苯磺酸氨氯地平片在健康人体的生物等效性

目的 研究苯磺酸氨氯地平片(抗高血压药)的相对生物利用度,并求证该制剂的生物等效性.方法 24名男性健康受试者随机交叉给药,先后口服单剂量试验制剂及参比制剂苯磺酸氨氯地平片剂5 mg,采用LC-MS/MS法测定血药浓度,计算2者的药代动力学参数及相对生物利用度,并评价2制剂的生物等效性.结果 口服试验制剂及参比制剂5 mg的主要药代动力学参数如下:t1/2分别为(47.15±17.28)、(43.22 ± 16.63)h;tmax分别为(5.81±2.09)、(6.38±2.33)h;Cmax分别为(4.77±1.28)、(4.37±1.14)ng·mL-1;AUC0-t分别为(176.39±57.95)、(182.55±58.36)ng·mL-1h;AUC0-t分别为(185.65±59.01)、(192.83±62.72)ng·mL-1h;试验制剂对于参比制剂的平均相对生物利用度F值:AUC0-t为(98.1±18.5)%,AUC0-∞为(98.6±20.0)%;tmax经非参数检验无显著性差异,试验制剂的平均生物利用度(AUC0-t、AUC0-∞)均大于98%,2种制剂的Cmax、AUC0-t和AUC0-∞双向单侧t检验和[1-2α]置信区间法的等效性分析均为合格,tmax经非参数秩和检验无显著性差异.结论 2种氨氯地平片剂为生物等效制剂.     

石杉碱甲缓释片多剂量给药在健康人体的生物等效性

目的 研究石杉碱甲缓释片(中枢兴奋药)多剂量给药在健康人体的相对生物利用度及生物等效性.方法 采用双周期自身随机交叉试验设计.24名健康受试者多次口服试验制剂或参比制剂,用液相色谱-串联质谱测定血浆中药物浓度,药代动力学参数用DAS软件处理获得.结果 试验制剂石杉碱甲缓释片组与参比制剂石杉碱甲片组的Cmin(ss)分别为(0.54±0.21)和(0.78±0.20)ng·mL-1;Cmax(ss)分别为(1.65±0.45)和(1.83±0.37)ng·mL-1;Css分别为(1.05±0.28)和(1.22±0.28)ng·mL-1;tmax分别为(3.50±1.90)和(1.10±0.40)h;AUC0-t(ss)分别为(30.70±8.20)和(35.10±8.93)ng·h·mL-1;AUC0-∞(ss)分别为(36.90±10.30)和(41.30±11.10)ng·h·mL-1;AUCss分别为(25.30±6.80)和(14.60±3.41)ng·h·mL-1;受试制剂的生物利用度F0-tn为(87.7±11.6)%.受试制剂和参比制剂的AUC0-t和AUC0-∞经对数转换后进行方差分析,2制剂间无显著性差异(P＞0.05).2制剂间tmax有显著差异(P＜0.05),受试制剂tmax明显比参比制剂有所延长,具有缓释的特征.结论 国产石杉碱甲缓释片与石杉碱甲片具有生物等效性,同时受试制剂具有明显的缓释特征.     

盐酸美金刚片在中国健康人体的生物等效性

目的:评价国产与进口盐酸美金刚片在中国健康人体的生物等效性。方法:20名健康男性受试者随机交叉单剂量口服受试制剂或参比制剂盐酸美金刚片各10mg。用高效液相色谱-串联质谱法测定血浆中美金刚浓度;用DAS3.0软件计算药动学参数,并对两种药物进行生物等效性评价。结果:受试制剂和参比制剂的主要药动学参数:Cmax分别为(18.1±3.8)和(20.3±4.2)ng·mL-1;tmax分别为(12.7±15.1)和(8.8±3.0)h;t1/2分别为(60.8±15.5)和(61.4±19.2)h;AUC0-t分别为(1 748.6±338.9)和(1 720.2±317.3)ng·h·mL-1。AUC0-t、AUC0-∞、Cmax的90%置信区间分别为89.8%～105.6%、89.7%～106.1%、84.8%～93.9%。受试制剂相对生物利用度F0-t为(95.5±2.9)%。结论:受试制剂与参比制剂具有生物等效性。     

洛伐他汀胶囊在健康人体的生物等效性研究

目的:考察两种洛伐他汀胶囊在健康人体的生物等效性.方法:20名健康男性志愿者单剂量口服试验制剂或参比制剂,采用LC/MS/MS法测定全血中药物浓度,用DAS2.1软件计算药代动力学参数.结果:试验制剂和参比制剂的主要药代动力学参数如下:t1/2分别为(4.67±2.34),(5.30±2.62)h;tmax分别为(1.90±0.50),(2.13±0.39)h;Cmax分别为(8.37±0.84),(8.29±1.00)ng·mL-1;AUC0-t分别为(32.25±6.49),(32.71±7.59)ng.h·mL-1;AUC0-∞分别为(33.62±6.94),(34.71±8.62)ng·h·mL-1.试验制剂的相对生物利用度F=(99.60±8.30)%.结论:受试制剂和参比制剂具有生物等效性.     

液相色谱串联质谱法测定人血浆中氯沙坦/氢氯噻嗪的浓度及其人体相对生物利用度研究

目的 建立一种快速、灵敏的测定人血浆中氯沙坦/氢氯噻嗪(抗高血压药)浓度的高效液相色谱串联质谱法,并评价2种氯沙坦钾氢氯噻嗪片在健康志愿者体内的生物等效性.方法 20例健康男性志愿者,用随机双交叉试验方法,单剂量口服受试或参比氯沙坦钾氢氯噻嗪片(50 mg/12.5 mg),用HPLC-MS/MS法测定血浆中氯沙坦/氢氯噻嗪浓度.结果 20名健康男性受试者口服含氯沙坦钾50 mg、氢氯噻嗪12.5 mg的受试制剂和参比制剂后,氯沙坦:tmax分别为(1.09±0.56)、(1.12±0.55)h,Cmax分别为(118.9 ±68.9)、(110.2±51.0)μg·mL-1,t1/2分别为(3.15±0.76)、(2.96±0.71)h,AUC0-t分别为(22.2±65.0)、(241.9±77.4)ng·h·mL-1,AUC0-t分别为(250.5±68.7)、(265.7±81.5)ng·h·mL-1;氢氯噻嗪:tmax分别为(1.93±0.54)、(2.25±0.60)h,Cmax分别为(73.2±11.0)、(74.5±17.4)ng·mL-1,t1/2分别为(9.45±3.57)、(8.33±2.58)h,AUC0-t分别为(401.8±138.3)、(390.6±149.3)ng·h·mL-1,AUC0-∞分别为(438.2±146.8)、(415.5±156.1)ng·h·mL-1.以氯沙坦AUC0-t计算,氯沙坦钾氢氯噻嗪片中氯沙坦与氢氯噻嗪相对生物利用度分别平均为(96.5±21.2)、(106.8±22.9)%.结论 受试制剂与参比制剂在人体内具有生物等效性.     

奥硝唑片在健康人体的生物等效性

目的 评价奥硝唑片(抗厌氧菌药)试验制剂与国产上市剂型在健康人体的生物等效性.方法 22例健康男性受试者随机分组,按照自身对照单次口服奥硝唑片1500 mg后,用高效液相色谱法测定血浆中奥硝唑的浓度,采用DAS软件计算主要药代动力学参数.结果 试验制剂和参比制剂的主要药代动力学参数如下:t1/2分别为(13.69±3.20)h和(14.31±4.30)h;tmax分别为(1.89 ±1.26)h和(1.73±1.10)h;Cmax分别为(29.13±3.57)μg·mL-1和(28.22±4.19)μg·mL-1;AUC0-t分别为(619.3±98.9)μg·h·mL-1和(601.1±92.9)μg·h·mL-1;AUC0-∞分别为(626.4±102.0)μg·h·mL-1和(609.0±94.3)μg·h·mL-1.试验制剂对于参比制剂的平均相对生物利用度F按照AuC0-t与AUC0-∞计算分别为(103.4±10.1)%,(103.2±10.1)%.结论 试验制剂和参比制剂为生物等效性制剂.同时2种制剂服用安全,耐受性良好.     

替吉奥胶囊(S-1)在中国癌症患者体内的药代动力学和生物等效性

目的 研究替吉奥胶囊(S-1,抗肿瘤药)在中国癌症患者体内的药代动力学特性并评价其生物等效性.方法 21名癌症患者随机交叉单剂量口服替吉奥胶囊(受试制剂)和爱斯万(参比制剂)各50 mg后,采用液相色谱-串联质谱法测定血浆中替加氟、5-氟尿嘧啶、吉美嘧啶和奥替拉西的浓度,并进行药代动力学和生物等效性研究.结果 受试者口服受试制剂和参比制剂后,血浆中替加氟的Cmax分别为(1887.0±491.0)和(1876.0±522.0)ng·mL-1;t1/2分别为(11.5±5.3)和(11.6±5.0)h;AUC0-t分别为(20.8±9.6)和(19.8±10.0)μg·h·mL-1.5-氟尿嘧啶的Cmax分别为(121.8±44.3)和(119.7±45.1)ng·mL-1;t1/2分别为(2.2±1.8)和(2.1±1.6)h;AUC0-t分别为(591.2±176.2)和(580.1±186.9)ng·h·mL-1.吉美嘧啶的Cmax分别为(304.6±107.3)和(297.2±103.6)ng·mL-1;t1/2分别为(4.1±1.8)和(4.0±2.5)h;AUC0-t分别为(1458.0±1094.0)和(1410.0±1043.0)ng·h·mL-1.奥替拉西Cmax分别为(77.4±77.3)和(79.9±73.4)ng·mL-1;t1/2分别为(4.7±2.7)和(4.3±2.0)h;AUC0-t分别为(403.7±333.2)和(427.8±377.3)ng·h·mL-1.受试制剂中替加氟、5-氟尿嘧啶、吉美嘧啶和奥替拉西的相对生物利用度分别为(108.1±23.6)%,(104.9±24.2)%,(107.2±23.9)%和(103.4±39.0)%.结论 AUC0-t、AUC0-∞和Cmax经对数转换后,应用方差分析法、双单侧t检验及90%信区间判断,2制剂具有生物等效性.     

进口与国产利培酮薄膜衣片在健康志愿者的生物等效性

目的 研究利培酮薄膜衣片(抗精神分裂症药)在健康志愿者的药代动力学和生物等效性.方法 23名健康男性志愿者随机交叉、单剂量口服受试制剂(进口)和参比制剂(国产)2 mg后,用HPLC-MS/MS测定血浆中利培酮及9-羟基利培酮浓度,计算主要药代动力学参数,评价2种制剂的生物等效性.结果 受试制剂和参比制剂的主要药代动力学参数,利培酮:AUC0～t分别为(94.76±82.93)和(103.05±117.71)ng·h·mL-1;AUC0～1分别为(96.72±84.52)和(105.19±119.36)ng·h·mL0-1;Cmax分别为(15.91±5.63)和(16.21±11.56)ng·mL-1;tmax分别为(1.14±0.73)和(1.15±0.54)h;t1/2分别为(7.32±5.94)和(7.44±6.50)h,受试制剂的相对生物利用度为(106.68±40.21)%.9-羟基利培酮:AUC0-96h分别为(268.56±85.20)和(279.64 ±117.86)ng·h·mL-1;AUC0-∞分别为(282.74±87.46)和(294.28±120.32)ng·h·mL-1;Cmax分别为(10.84±4.69)和(11.11±4.80)ng·mL-1;tmax分别为(3.35±2.32)和(4.48±2.76)h;t1/2分别为(23.18±3.26)和(23.12±4.31)h,受试制剂的相对生物利用度为(101.37±27.23)%.结论 2种制剂具有生物等效性.     

小儿氨酚伪麻分散片在健康人体的生物等效性

目的研究小儿氨酚伪麻分散片和氨酚伪麻滴剂(解热镇痛药)在健康人体内的药代动力学和生物等效性。方法用随机单剂量交叉,22名男性受试者口服试验药和对照药350mg后,用高效液相色谱法测定血药浓度,计算其药代动力学参数和相对生物利用度,评价2种制剂的生物等效性。结果试验药和对照药的药代动力学参数,盐酸伪麻黄碱:t1/2ke分别为(4.21±0.70),(4.16±0.97)h;tmax分别为(1.27±0.42),(1.36±0.58)h;Cmax分别为(144.65±30.56),(148.56±29.99)ng.mL-1,AUC0-12分别为(840.35±171.14)(841.33±177.70)ng.h.mL-1;AUC0-∞分别为(983.19±213.43),(988.98±235.31)ng.h.mL-1;F(AUC0-12)为(103.04±26.54)%,F(AUC0-∞)为(102.79±26.85)%。对乙酰氨基酚:t1/2ke分别为(2.95±0.50),(3.05±0.54)h;tmax分别为(0.57±0.35),(0.49±0.22)h;Cmax分别为(5.15±1.07),(5.43±1.45)μg.mL-1;AUC0-12分别为(17.60±3.71),(19.21±5.72)μg.h.mL-1;AUC0-∞分别为(18.90±4.24),(20.67±6.45)μg.h.mL-1;F(AUC0-12)为(95.02±18.58)%,F(AUC0-∞)为(94.83±18.23)%。结论2种制剂具有生物等效性。     

Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol

OBJECTIVE: Bosentan has been shown in vitro and in vivo to induce the cytochrome P450 enzymes CYP2C9 and CYP3A4. The present study was conducted to investigate the effect of bosentan on the pharmacokinetics of a combined oral contraceptive. SUBJECTS AND METHODS: In a randomized, 2-way crossover study, 20 healthy female subjects received Treatments A and B. Treatment A consisted of a single dose of OrthoNovum containing 1 mg norethisterone (norethindrone) and 35 microg ethinyl estradiol. Treatment B consisted of bosentan, 125 mg b.i.d. for 7 days plus concomitant norethisterone and ethinyl estradiol on Day 7. Plasma concentrations of norethisterone and ethinyl estradiol were measured on days of oral contraceptive administration. RESULTS: In the absence of bosentan, the pharmacokinetics of norethisterone and ethinyl estradiol were characterized by Cmax and AUC0-infinity values (95% CI) of 9.8 (8.1, 11.9) ng/ml and 72.9 (57.0, 93.1) ng x h/ml, and 53.0 (47.0, 59.9) pg/ml and 758 (655, 878) pg x h/ml, respectively. Concomitant bosentan did not affect the Cmax but significantly decreased the AUC of norethisterone and ethinyl estradiol by 13.7% (-23.5, -2.6) and 31.0% (-40.5,-20.2), respectively. The maximum decrease in AUC of norethisterone and ethinyl estradiol in an individual subject was 56% and 66%, respectively. CONCLUSIONS: Bosentan decreases the AUC of norethisterone and ethinyl estradiol in healthy female subjects. In patients treated with bosentan, reduced efficacy of hormonal contraceptives should be considered.     

高效液相色谱法测定复方戊酸雌二醇片中戊酸雌二醇和炔诺酮的含量

目的：建立用高效液相色谱法测定复方制剂中戊酸雌二醇和炔诺酮含量的方法。方法：用氰基键合硅胶为固定相，乙腈-水(47：53)为流动相，黄体酮为内标，UV检测波长为280m。结果：该方法回收率为戊酸雌二醇100．6％，RSD=0．9％(n=9)，炔诺酮100．2％，RSD=0．8％(n=9)；测定了三批样品，结果满意。结论：该法不需经复杂的样品处理，简便、快速，准确可靠，可作为该复方制剂的含量测定方法。     

Endogenous estradiol metabolism during treatment with oral contraceptives

OBJECTIVE: Recent clinical studies indicate that an increase in D-ring estradiol metabolites over A-ring metabolites may be a risk factor for breast cancer. The present work was aimed to investigate the effect of oral contraceptives (OC) on the endogenous estradiol metabolism in premenopausal women. METHODS: Two studies were conducted, firstly comparing 2 different progestins, i.e. norethisterone and dienogest, each in combination with a constant ethinyl estradiol dosage (study A) and secondly comparing a single progestin, i.e. levonorgestrel in 2 ethinyl estradiol/progestin dosage combinations (study B). The main A- and D-ring metabolites, i.e. 2-OHE1 and 16-OHE1, were measured by enzyme immunoassay in 8-h night-urine collected before and after 3 cycles of OC administration. RESULTS: In study A, i.e. ethinyl estradiol plus dienogest or norethisterone acetate, the ratios of 16-OHE1 to 2-OHE1 before administration were 0.62 and 0.68, and after 3 months 0.31 and 0.54, respectively. The ratio after ethinyl estradiol and dienogest was significantly lower after treatment. In study B, i.e. ethinyl estradiol plus levonorgestrel (0.03 mg/0.15 mg and 0.02 mg/0.1 mg), the ratios before treatment were 0.71 and 0.75 for the higher and the lower dosages, respectively, which changed not significantly to 0.73 and 0.71 after 3 cycles. CONCLUSION: OCs containing norethisterone acetate, dienogest or levonorgestrel did not have a negative effect on estradiol metabolism, i.e. they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.     

Estradiol valerate/dienogest

Estradiol valerate 2mg/dienogest 2mg is an oral estrogen/ progestogen formulation that has been approved throughout the European Union for the treatment of climacteric symptoms in postmenopausal women. Dienogest is a progestogen that combines the properties of both progesterone and 19-nortestosterone derivatives. It has moderate affinity for the progesterone receptor, significant antiproliferative and antiandrogenic activity, and produces secretory transformation of the endometrium. Estradiol valerate is an esterified form of natural 17beta-estradiol, the most potent endogenous human ovarian estrogen, and is hydrolysed to estradiol soon after oral administration. Results from a randomised, double-blind, multicentre trial showed that oral estradiol valerate 2mg/dienogest 2mg and estradiol valerate 2mg/dienogest 3mg once daily for 1 year were each as effective as estradiol 2mg/estriol 1mg/norethisterone acetate 1mg in the treatment of climacteric symptoms in 581 postmenopausal women; reductions from baseline in Kupperman Index scores were 78.5, 74.5 and 75.0%, respectively. The number of days without any type of bleeding was lowest in patients treated with estradiol valerate 2mg/dienogest 2mg (8.7 days), and highest in the estradiol valerate 2mg/ dienogest 3mg group (12.1 days). During the twelfth month of treatment with estradiol valerate 2mg/dienogest 2mg, the percentage of patients who reported bleeding was 14.5%. Endometrial biopsy results were similar in patients treated with estradiol valerate 2mg/dienogest 2mg, estradiol valerate 2mg/dienogest 3mg or estradiol 2mg/estriol 1mg/norethisterone acetate 1mg once daily for 1 year; 90.8, 87.4 and 87.5% of samples, respectively, contained atrophic material. Proliferative material was found in 4.2, 2.5 and 4.4% of the biopsies, respectively; there was no incidence of hyperplasia in any of the treatment groups. A noncomparative multicentre study in 1501 postmenopausal women demonstrated that adverse events associated with estradiol valerate 2mg/dienogest 2mg once daily for 48 weeks included breakthrough bleeding, mastalgia, headache, abdominal pain, hypertension, thrush, migraine, weight gain, increase in endometrial thickness and metrorrhagia.     

中国西部健康人群口服替诺福韦富马酸酯片的药动学研究

目的:研究口服替诺福韦富马酸酯片在中国西部健康人群的药动学特征。方法:24名健康志愿者随机分为3组,每组8人,分别给予替诺福韦富马酸酯片300mg、恩曲他滨胶囊200mg+替诺福韦富马酸酯片300mg、脂肪食物(食物中脂肪比例50%)+替诺福韦富马酸酯片300mg,分别在服药前0h及服药后0.5、0.75、1、1.5、2、3、4、6、8、12、24、36、48、72h时取静脉血2mL,分离血浆,采用固相萃取,以高效液相色谱-紫外(HPLC-UV)法测定替诺福韦血药浓度,以DAS(Ver2.1.1)软件计算药动学参数。结果:3组药动学参数分别为:t1/(218.78±3.28)、(12.72±2.83)、(13.08±1.47)h,tma(x1.05±0.16)、(1.28±0.30)、(1.55±0.37)h,cma(x290.71±63.21)、(420.84±96.71)、(429.06±174.81)ng·mL-1,AUC0～7(21871.60±377.00)、(3869.42±962.85)、(3569.47±633.47)μg·h·L-1,AUC0～∞(2284.16±373.54)、(4107.09±974.82)、(3856.00±618.39)μg·h·L-1,CL/F(2.25±0.39)、(1.28±0.28)、(1.33±0.20)L·h-1·kg-1。与替诺福韦富马酸酯组比较,恩曲他滨+替诺福韦富马酸酯组、脂肪食物+替诺福韦富马酸酯组的t1/2降低,cmax、AUC0～72、AUC0～∞、tmax均明显增加。结论:中国西部人群单独给予替诺福韦富马酸酯的药动学特征与国外人群相似,高脂肪饮食以及合用恩曲他滨可改变替诺福韦的药动学特征。     

地非三唑与甾体激素类药物的体外相互作用

目的观察地非三唑与甾体激素类药物的代谢性相互作用，为临床合理用药提供科学依据。方法选择在临床上可能与地非三唑合用的甾体激素类药物，如米非司酮、雌二醇、醋酸甲羟孕酮、黄体酮和炔诺酮等进行试验。分别将它们与地非三唑在鼠肝微粒体中共孵育，采用反相高效液相色谱法测定孵育液中地非三唑和共孵育药物的剩余浓度或代谢产物浓度，计算代谢抑制常数值。结果地非三唑对米非司酮、雌二醇、醋酸甲羟孕酮、黄体酮以及炔诺酮的代谢抑制常数K_i分别为(201.3±1.0)，(94±4)，(128.7±2.2)，(64±5)和(80±4) μmol·L^-1；雌二醇、醋酸甲羟孕酮、黄体酮以及炔诺酮对地非三唑的代谢抑制常数K_i分别为(66.9±2.2)，(60.0±2.3)，(163±10)和(88±5) μmol·L^-1。结论地非三唑与甾体激素类药物之间均有不同程度的代谢相互抑制作用。     

Study of plasma renin activity in Indian women using low estrogen combination pill as contraceptive [abstract

Comgination oral contraceptives (OCs) containing ethinyl estradiol 0.05 mg and norethisterone 1 mg is known to cause various metabolic changes and hypertension is 1 of them. Both plasma renin activity (PRA) and angiotensin are considerably increased during pregnancy and these changes are attributed to estrogen induced changes in renin substrate. Recently OCs containing less amount of estrogen are in use and this study reports PRA levels in Indian women taking pills containing 0.03 mg ethinyl estradiol and 1 mg norethistrone. PRA was estimated by radioimmunoassay method in a matched control group and compared with those taking OCs for different durations. Analysis of the data revealed that the mean values for PRA in those taking the low estrogen OC pills were significantly higher than the control group of women not taking the OC.     

HPLC法测定炔诺酮片含量及含量均匀度的不确定度分析

目的:建立测定炔诺酮片含量及含量均匀度不确定度的分析方法。方法:采用高效液相色谱法测定含量及建立含量均匀度的数学模型,确定影响不确定度的因素并对各个不确定度因素进行评估。结果:炔诺酮片含量和含量均匀度测定的合成不确定度均为1.2%,扩展不确定度均为2.4%,结果分别为(101.8±2.4)%、(102.3±2.4)%。结论:本方法可用于该制剂含量及含量均匀度的不确定度分析。     

The effect of food on the bioavailability of norethindrone and ethinyl estradiol from norethindrone acetate/ethinyl estradiol tablets intended for continuous hormone replacement therapy

As part of the development of a combination product containing norethindrone acetate and low-dose ethinyl estradiol for continuous hormone replacement therapy in postmenopausal women, a study was conducted to determine the effect of a high-fat meal on the bioavailability of norethindrone and ethinyl estradiol from tablets containing 1 mg norethindrone acetate/10 micrograms ethinyl estradiol. Eighteen healthy postmenopausal women participated in an open-label, single-dose, randomized, three-way crossover study in which 2 x 1/10 norethindrone acetate/ethinyl estradiol tablets were administered fasting and with a high-fat breakfast, and the same dose was administered in solution. Following each treatment, serial blood samples were collected for 48 hours, and plasma ethinyl estradiol and norethindrone concentrations were determined by a validated gas chromatography/mass spectrometry (GC/MS) method. Individual plasma ethinyl estradiol and norethindrone pharmacokinetic parameters were calculated by noncompartmental methods for each treatment and analyzed by ANOVA to obtain differences between least squares treatment mean values and associated 90% confidence intervals. Rates of ethinyl estradiol and norethindrone availability from tablets administered with food were slower than availability rates from tablets administered while fasting. Systemic exposure to ethinyl estradiol was unaffected by administration of tablets with food, whereas exposure to norethindrone increased by 27%. Because administration of norethindrone acetate/ethinyl estradiol 1/10 tablets with a high-fat meal did not decrease systemic exposure to norethindrone and ethinyl estradiol, this formulation can be taken without regard to meals.     

Voltammetry and quantification of the contraceptive drug norethisterone in bulk form and pharmaceutical formulation

The electrochemical behavior of norethisterone at the mercury electrode was studied in the universal buffer of various pH values using dc-polarography, cyclic voltammetry and controlled-potential electrolysis. Norethisterone was reduced at the mercury electrode via the consumption of two electrons corresponding to reduction of the 3-keto-delta-4-group in the A-ring of the molecule. The pK(a) value (8.7) of norethisterone was determined from the polarographic and spectrophotometric measurements. A fully validated, simple, sensitive, precise and inexpensive square-wave adsorptive cathodic stripping (SWAdCS) voltammetry procedure was described for trace quantification of bulk norethisterone. The stripping voltammetry peak current of norethisterone in a universal buffer of pH 5 following its accumulation onto the hanging mercury drop electrode (HMDE) at -0.6 V (versus Ag/AgCl/KCl(s)) for 130 s showed a linear response with the concentration over the range 5 x 10(-9) to 3 x 10(-7)M norethisterone. Detection and quantitation limits of 1.5 x 10(-9) and 5 x 10(-9)M bulk norethisterone, respectively, were achieved. The proposed procedure was successfully applied for the assay of norethisterone in Steronate tablets without interference from excipients.