目的 开发与格列美脲片体内溶出行为相关的体外溶出方法,并预测两种片剂的人体生物等效性.方法 采用GastroPlusTM软件建立格列美脲片人体药代动力学(PK)模型;基于模型预测原研片剂在人体中的溶出行为;以预测结果指导体外溶出方法开发;通过虚拟生物等效性试验,利用体外溶出数据预测B、C两种格列美脲片的人体生物等效性(BE)结果;利用比格犬BE进行佐证.结果 模型的准确性与可靠性良好;原研片剂在人体胃肠道中呈线性溶出,于2h时溶出完全;流通池开环模式(pH 7.0缓冲液,14 mL·min-1)可基本模拟格列美脲片在人体中的溶出行为;经虚拟生物等效性试验,预测B与原研片剂生物等效,而C与其不等效;比格犬BE试验结果与人体虚拟BE结果一致.结论 基于体外溶出数据,预测格列美脲片人体生物等效性的方法具有一定可行性.

杂质影响药物的稳定性和质量,降低疗效,并带来可能的毒副作用,分析并控制杂质含量对保证药物质量和用药安全十分重要,是新药研发和仿制药质量疗效一致性评价的一项重要内容.本文以临床抗高血压一线用药二氢吡啶类药物为例,讨论了杂质研究所涉及的杂质来源、检测方法、杂质限度以及评价标准等相关内容,并对可能出现的问题提出了解决建议,为药物的杂质研究提供参考.

为改善我国部分仿制药质量与国际先进水平还存在一定差距的现状,《国家药品安全”十二五”规划》中明确提出了开展仿制药一致性评价,全面提高仿制药质量的任务.氯雷他定片作为抗过敏药物的主要品种之一,需在2018年底前完成一致性评价.基于现有质量和疗效一致性评价指导原则与相关研究报道,针对氯雷他定原料药的晶型研究、原辅料杂质的比较研究、片剂溶出曲线的比较方法以及生物等效性试验研究等进行了总结和概括,并对有待解决的共性问题进行了讨论.

目的 建立大鼠血浆中奥氮平和盐酸氟西汀的LC-MS/MS同时测定方法.方法 血浆样品在碱性条件下用乙醚提取浓缩后,采用XDB-CN(2.1 mm'150 mm I.D.,5μm)柱进行分离,流动相为乙腈-10 mmol/L乙酸铵(pH=4.0)=55:45 (v/v);ESI选择性反应正离子模式检测,氯雷他定作为内标.结果 奥氮平在0.25～400 ng/mL范围内相关系数r=0.9979,最低检测限为0.10 ng/ml,日内、日间精密度分别为2.26％～ 8.38％及3.54％～7.37％;盐酸氟西汀在0.50～ 800ng/ml范围内相关系数r=0.9976,最低检测限为0.20 ng/ml,日内、日间精密度分别为1.03％～2.52％及3.26％ ～ 7.29％.结论 本方法灵敏度高、专属性强、准确性好,符合生物样品的分析要求.

Objective To establish a rapid LC-MS/MS method for simultaneous determination of zofenopril and its active metabolite zofenoprilat in human plasma.Methods In plasma samples,1,4-dithiothreitol (DTT) was added as a stabilizer to protect the thiol group of zofenoprilat,and diazepam was used as internal standard (IS).The plasma samples were liquid-liquid extracted with methyl tert-butyl ether in acid medium,then separated on C8 column (2.1 × 150 mm I.D.,3.5μm) and detected by triple-quadruple tandem mass spectrometer in the selected reaction monitoring (SRM) mode.Methanol and 0.1％ formic acid solution (85∶ 15,v/v) were used as mobile phase,with a flow rate of 0.2 ml/min.Results The linear range of zofenopril was 0.20-800 ng/ml with r =0.995 4,and the limit of detection was 0.1 ng/ml.The intra-and inter-batch standard deviations were in the range of 1.00％ ～6.06％ and 3.66％ ～ 5.97％,respectively.The linear range of zofenoprilat was 0.50-2 000 ng/ml with r =0.999 4,and the limit of detection was 0.25 ng/ml.The intra-and inter-batch standard deviations were in the range of 0.91％ ～ 7.05％ and 2.92％ ～7.29％,respectively.Conclusion The method is simple and sensitive,which makes it suitable for determination of zofenopril and zofenoprilat in human plasma.

An LC-MS/MS method was developed to investigate the pharmacokinetic parameters in healthy Chi-nese volunteers following single and multiple oral administration of dimemorfan phosphate. In the Single-dose study,two-period and crossover study was conducted in 12 healthy volunteers,which were administered with single-dose of 10 mg or 40 mg of dimemorfan phosphate. And another 12 volunteers were administered with 20 mg. The values of AUC0-48 h,t1/2,and cmax were (11. 81 ±14. 46),(52. 60 ±96. 01 )and (34. 70 ±29. 59)ng. h/mL,(12. 11 ±2. 54),(12. 16 ±2. 01)and (12. 77 ±1. 27)h,and (0. 9653 ±0. 8178),(3. 150 ±3. 451)and (2. 167 ±1. 650)ng/mL for 10 mg,40 mg and 20 mg oral administration. The same 12 healthy volunteers as the group of single-dose of 20mg were participated in multiple-dose study,which were administered dimemorfan phos-phate 20 mg,three-time a day until the day-8,showed AUC0-48 h,t1/2,and cmax were (115. 9 ±135. 2)ng.h/mL, (11. 22 ±1. 61)h,and (7. 418 ±7. 010)ng/mL. The accumulation parameter Rcmax and RAUC was (3. 14 ±1. 34) and (3. 38 ±1. 22),respectively. Dose proportional of cmax and AUC was not concluded ranging from 10 mg to 40 mg after confidence interval criteria method. An accumulation was occurred after multiple -dose administra-tion with the consequence. And the results demonstrated significant individual difference.

目的 建立超高效液相-二极管阵列-离子阱-飞行时间串联质谱(UPLC-DAD-IT-TOF-MS)法分离鉴定甘草酸二铵肠溶片中相关杂质的分析方法.方法 采用Agilent HC-C18(250 mm×4.6 mm,5μm)色谱柱,以乙腈-水-冰醋酸(380∶614∶6)为流动相等度洗脱样品,体积流量1 mL/min,紫外检测波长254nm,质谱监测质荷比范围m/z 100～1 000.结果 分离鉴定出甘草酸皂苷G2、H2、E2、B2、J2、C2及18α-甘草酸、乌拉尔甘草皂苷(A或B)8种有关物质.结论 研究结果为甘草酸二铵肠溶片的质量控制和工艺优化提供了依据,同时为中药制剂的杂质鉴定提供可借鉴的分析思路.

非洛地平和辛伐他汀在临床上广泛被联合使用,然而并未见关于二者相互作用的研究报道,本研究旨在从体内和体外两方面研究辛伐他汀对非洛地平的代谢和口服药代动力学的影响。非洛地平和辛伐他汀在大鼠肝微粒体中共温孵,结果表明辛伐他汀是非洛地平的非竞争性抑制剂,抑制常数Ki=（9.86±0.27）μmol/L。12只大鼠随机分为两组,Ⅰ组灌服非洛地平;Ⅱ组灌服非洛地平和辛伐他汀。大鼠同时灌服非洛地平和辛伐他汀后,测得非洛地平的cmax和AUC0-∞显著增加,清除率（CLz/F）显著降低,而平均驻留时间（MRT0-∞）和半衰期（t1/2）无显著性变化。结果表明辛伐他汀促进了非洛地平在大鼠体内的吸收。该实验为非洛地平和辛伐他汀可能存在的药物相互作用提供了理论参考。

Objective:To investigate the pharmacokinetic interaction between ibuprofen and lafutidine in rats before and after drug combination.Method:LC-MS/MS method was developed for determination of ibuprofen and lafutidine,DAS 2.0 for calculation of pharmacokinetic parameters.Result:The parameters have no significant difference.Conclusion:There were no drug-drug interaction.The dose and interval need not be changed when co-administered.

建立了高效液相色谱-串联质谱分析方法,分析大鼠灌服枳实提取液后尿液、粪便和胆汁中的黄酮类成分。采用色谱柱为Agilent Zorbax SB-C18柱（250mm×4.6mm,5μm）;流动相为0.1%甲酸水溶液-甲醇-乙腈三元梯度洗脱系统,柱温35℃,流速1.0mL/min;采用电喷雾离子化源-三重四极杆质谱系统,负离子模式检测。在枳实提取液中共检出了34种黄酮类成分,在大鼠生物样本中共检出40种黄酮类成分,其中14种来源于体外,26种为代谢产物,并初步归属了它们的结构。

OBJECTIVE To study the pharmacokinetics of mitiglinide in healthy Chinese volunteers and estimate its main pharmacokinetic parameters.METHODS The study was parallel designed.A single dose of mitiglinide of 5,10 and 20 mg was administrated to 12 healthy volunteers in three periods,respectively.The plasma concentrations of mitiglinide which were used to estimate pharmacokinetic parameters were determined by LC-MS.RESULTS The pharmacokinetic parameters of 5,10 and 20 mg mitiglinide were as follows:ρmax(742.86±272.60),(1 447.42±590.64)and(2 614.43±721.09)μg.L-1;tmax(0.32±0.12),(0.34±0.11)and(0.35±0.11)h;t1/2(1.61±0.39),(1.91±0.66)and(1.70±0.38)h;AUC0-12(1 006.27±218.09),(1 928.35±596.17)and(3 677.82±901.27) μg.h.L-1.CONCLUSION The absorption,distribution,metabolism and excretion of mitiglinide in human body coincide with the process of first-order kinetics.The results indicated the pharmacokinetic linearity of three dosages was within the studied dose range.

Objective To compare the bio-availability between test gliclazide sustained release tablet and commercially available reference tablet.Methods A HPLC/MS method was developed and used to determine gliclazide plasma concentrations of 20 healthy volunteers in an open randomized two-way crossover test after single oral dose and multiple oral doses.The pharmacokinetic parameters were estimated.Results After single oral gliclazide sustainde release tablets of reference (30mg) or test (30mg) drugs were given,gliclazide plasma concentration against time was calculated and evaluated.The main pharmacokinetic parameters after a single oral dose of test versus reference drug were as follows: Cmax was 1.21±0.26 vs 1.09±0.24μg/ml,Tmax was 7.4±1.8 vs 7.0±1.6h,AUC0～72 was 26.23±8.65 vs 25.88±8.87μg·h·ml-1,respectively,AUC0~∞ was 27.65±9.80 vs 27.12±9.90μg·h·ml-1. The Cmax,Cmin,Cav,Tmax,DF,AUCss of gliclazide test versus reference tablets after multiple oral doses were 1.37±0.49 vs 1.31±0.41μg/ml;0.069±0.075 vs 0.060±0.066μg/ml;0.41±0.20 vs 0.42± 0.19μg/ml;6.0±1.7 vs 6.6±2.6h;3.46±0.99 vs 3.29±1.06;29.66±14.10 vs 29.95±13.40μg·h ·ml-1 respectively.The AUC and AUCss were tested after natural logarithmic transformation and no difference with statistical significance was found.Conclusions The test formulation is bioequivalent to the reference formulation for gliclazide.

Aim:To investigate the pharmacokinetics and relative bioavalability of compound loratadine sustained-release capsules in healthy chinese volunteers.Methods:The concentrations of loratadine and pseudoephedrine sulfate in plasma were determined by LC-MS after oral administration of a single and multiple oral doses of the test capsules and references tablets.The pharmacokinetic parameters were estimated by BAPP 2.2 software.Results:The concentration-time curves of two formulations were successful fitted to a one-compartment open model.In the single dose,the relative bioavailabilities of loratadine and pseudoephedrine sulfate were(97.6±17.4)% and(98.8±15.5)%,respectively.In the multiple doses,they were(94.6±16.0)% and(94.4±13.9)%,respectively.Conclusion:The test capsules are found to be bioequivalent to the reference tablets in the term of the AUC,but the c_(max) and t_(max) of pseudoephedrine sulfate are significantly different.

AIM: To develop an analytical method based on LC-MS/MS for the quantification of lisinopril in human plasma and the assessment of bioequivalence for two kinds of lisinopril tablets in Chinese healthy male volunteers. METHODS: Plasma samples of 20 healthy male volunteers, who were administrated with a single oral dose of lisinopril test tablets (10 mg) and reference tablets (10 mg) according to a random 2-way crossover design, were prepared by a simple protein precipitation and then were determined by LC-MS/MS method. RESULTS: The main pharmacokinetic parameters of lisinopril test tablets and reference tablets were as follows: cmax(54±s 21) and (53±23)μg·L-1, tmax(6.4±1.4) and (6.7±1.1) h, AUC0-36(569±244) and (566±269)μg·h·L-1, AUC0-∞(589±250) and (587±268)μg·h·L-1, respectively. Calculating by AUC0-36, the relative bioavailability of lisinopril test tablets was (102±8) %. CONCLUSION: The analytical method based on LC-MS/MS for quantification and assessment of bioequivalence is simple, rapid and sensitive, proving the bioequivalence of lisinopril test tablets to the reference tablets.

Aim: To develop an LC-MS method for the study of bioavailability and pharmacokinetics of tolterodine tartrate immediater-release tablets and extended-release tablets administered to Chinese healthy volunteers. Methods: After adding oxybutynin (internal standard), the plasma samples were extracted with a mixture of n-hexane-isopropanol (95:5, v/v) and determined by LC-MS. Chromatography was performed on the column of Shimadzu Shim-pack VP-ODS C18(150 mm × 2.0 mm ID) with the mobile phase of CH3CN-10 mmol/L NH4OAc, (50:50, v/v; adjusted to pH 3.0). Analyses were run at a flow rate of 0.2 mL/min. Detection was carriedout on a single quadrupole mass spectrometer by selected ion monitoring (SIM) mode via electrospray ionization (ESI) source. Based on a random two-way crossover design, 20 subjects were exposed to tolerodine tartrate extended-release tablets (ER) and the immediate-release ones (IR) after a single dose and multiple dose administrations. Results: The assay exhibited a linear range from 0.1 to 30.0 ng/mL with the correlation coefficient of 0.999 3 and the detection limit of 0.05 ng/mL. The results from the study of a single dose indicated that the cmax of IR was significantly higher than that of ER (P < 0.05) and that the tmax and t1/2 of ER was longer than those of IR. The relative bioavailability of ER was (107.3 ± 11.4)% compared with IR. In the multiple dose study, the degree of fluctuation (DF) of ER was less than that of IR. And the relative bioavailability of ER was (105.2 ± 21.5)%. Conclusion: The developed method proved simple, sensitive and rapid. The two formations have similar absorption extent. However, ER exhibited extended-release profile.

AIM:To establish a HPLC method for the study of bioavaibility and pharmacokinetics of metformin in human plasma. METHOD: A simple HPLC method using ultraviolet detection was developed, which entailed the direct injection of the plasma sample after deproteinating with 30% perchloric acid. The mobile phase consisted of 0.01M potassium dihydrogen orchophosphate(pH 4.0) and acetonitrile (65∶35, v/v ). Analysis was run at a flow-rate of 1.0 ml/min with the detector operated at wavelength 233nm. The mean absolute recovery value was above 90%, while the within-day and between-day coefficients of variation were less than 10%.The calibration curve was linear over a concentration range of 0.1 to 4.0 μg/ml. RESULT: The method was proved to be simple,sensitive and rapid.

目的:建立兔血浆中妥洛特罗的LC-MS定量方法,比较受试制剂和参比制剂中妥洛特罗主要药代动力学参数.方法:血浆中加入内标盐酸克伦特罗,碱化后经正己烷:异丙醇(95:5)混合溶剂提取,进行LC-MS测定.色谱柱为 Lichrospher CN(5 μm,150 mm×2.0 mm),流动相为甲醇-0.01 mol/L醋酸铵溶液(70:30),流速为0.2 mL/min;ESI选择性正离子检测.试验方案采用随机平行试验设计.结果:妥洛特罗血浆线性范围为0.5～40 ng/mL,检测限为0.1 ng/mL.测得受试贴剂与参比贴剂的主要药代动力学参数无显著性差异,受试贴剂的相对生物利用度为114.78%.结论:本方法专属性强,灵敏度高,准确性好.

AIM: To establish a HPLC-UV method for the study of pharmacokinetics and bioavailability of baicalin in human plasma. METHODS: The study was performed with 18 male volunteers according to a random 2-way cross-over design. Plasma samples of 18 male volunteers after oral administration of 750 mg baicalin test capsules and reference tablets were prepared by solid phase extraction and the concentrations of baicalin were determined by HPLC-UV method. Pharmacokinetic parameters were also estimated. RESULTS: The main pharmacokinetic parameters of baicalin test capsules and reference tablets were as follows: c_(max)(91±s 33)μg·L~(-1) and (86±29) μg·L~(-1), t_(max)(7.4±1.3) h and (7.4±1.0) h, AUC_(0-24)(586±233) μg·h·L~(-1) and(579±(173) μg·)h·L~(-1), AUC_(0-∞)(616±249) μg·h·L~(-1) and(613±180)μg·h·L~(-1), respectively. The relative bioavailability of baicalin test capsules was(101±(18) %). CONCLUSION: The HPLC-UV is proved to be simple, sensitive and rapid method showing the bio-( )equivalence of the two formulations.

目的拟订高效液相色谱法测定酚氯伪麻缓释片中对乙酰氨基酚血药浓度的方法.方法血浆样品前处理方法:取血浆0.5mL,加20%高氯酸100μL,涡旋离心取上清液,供HPLC/UV分析.色谱柱:PhenomenexLunaC18(150mm×4.6mmID);流动相:甲醇:水=H:86;检测波长271nm.结果对乙酰氨基酚血药浓度在0.2～20.0μg·mL-1范围,色谱响应线性关系良好,r=0.9994.最低检测限为0.1μg·mL-1;低、中、高3种浓度的平均提取回收率在90.3%～93.4%,方法回收率在101.6%～101.9%范围内.