Aim To evaluate the bioequivalence of two brands of losartan/hydrochlorothiazide （50 mg/12.5 mg） compound tablets in healthy Chinese male volunteers. Methods An open, randomized, single-dose, two-period cross-over s...Aim To evaluate the bioequivalence of two brands of losartan/hydrochlorothiazide （50 mg/12.5 mg） compound tablets in healthy Chinese male volunteers. Methods An open, randomized, single-dose, two-period cross-over study with a wash-out period of 7 d was conducted. Twenty healthy male volunteers were given a single dose 50 mg losartan/12.5 mg hydrochlorothiazide of either test （T） or reference （R） compound tablets, respectively. Blood samples were collected up to 48 h after oral administration. The concentrations of losartan and hydrochlorothiazide in plasma were determined by a validated HPLC-ESI-MS method. Results In the case of losartan, the 90% confidence intervals of two one-side test for percent ratios with a significant level （α） of 0. 05 were 86% - 112% for AUC0-12 and 89% - 134% for Cmax, respectively, which were within the interval proposed in the Chinese Pharmacopoeia, 80% - 125% of AUC and 70% - 143% of Cmax, respectively. Similarly, the 90% confidence intervals for percent ratios were 85% - 100% and 75% - 102% for hydrochlorothiazide, both of which fell into the accepted interval. Conclusion Two immediate-release compound tablets of losartan/hydrochlorothiazide are bioequivalent from a statistical standpoint in the extent and rate of absorption from the single-dose study in healthy Chinese male volunteers.展开更多
Background: Dienogest is a potential treatment for pelvic pain associated with endometriosis, a condition of significant concern in gynaecology. The current study was conducted as a crossover-randomized bioequivalence...Background: Dienogest is a potential treatment for pelvic pain associated with endometriosis, a condition of significant concern in gynaecology. The current study was conducted as a crossover-randomized bioequivalence assessment of two oral Dienogest 2 mg formulations, aiming to provide valuable insights for healthcare professionals and researchers in this field. Objective: The primary aim of this research was to evaluate and compare the pharmacokinetic characteristics of Dienogest 2 mg tablets. Dinogest (Dienogest 2 mg) tablets, manufactured by Nuvista Pharma Limited in Bangladesh, and Visanne (Dienogest 2 mg) tablets, manufactured by Bayer Pharma in Germany, were the test and reference formulations, respectively. Materials and Method: The study was an open-label, balanced, randomized, two treatments, two sequences, two periods, two-way crossover, laboratory blind, single oral dose bioequivalence study conducted in healthy adult females under fasting conditions. The study was carried out on 13 healthy, non-pregnant female subjects, and all the subjects completed both study periods with a 15-day washout in between. Randomization was used to assign the test and reference formulations to the subjects. Following each oral administration, a series of blood samples were obtained at different time intervals from pre-dose to 72 hours post-dose and analyzed for Dienogest concentrations using a validated bio-analytical method. A standard non-compartmental model was used to analyze the pharmacokinetic parameters. The primary pharmacokinetic parameters were peak plasma drug concentration (C<sub>max</sub>), the area under the plasma concentration-time curve from time zero to time t (AUC<sub>0–t</sub>), and AUC from t = 0 to infinity (AUC<sub>0–∞</sub>). The other PK parameters included time to reach C<sub>max</sub> (T<sub>max</sub>), terminal elimination rate constant (K<sub>el</sub>), and half-life (t<sub>1/2</sub>). Result: The ratios and 90% CI for the geometric mean test/reference were 95.53% (86.70% - 105.26%) for C<sub>max</sub>, 101.75% (95.42% - 108.49%) for AUC<sub>0</sub><sub>−</sub><sub>t</sub>, and 101.54% (95.59%% - 107.87%) for AUC<sub>0</sub><sub>−</sub><sub>∞</sub>. The formulations were bioequivalent since the 90% CIs for the geometric mean test/reference ratios were 80% to 125%, according to the predetermined range of US Food and Drug Administration (FDA) requirements. Conclusion: This single-dose investigation shows that the Dienogest test and reference formulations exhibited a rate and degree of absorption that met the regulatory requirements for bioequivalence.展开更多
Objective: To evaluate the bioequivalence (BE) of two fixed-dose combination (FDC) formulations of Rosuvastatin and Ezetimibe: Cresadex® EZE 20/10 mg (Abbott Laboratories) as the reference formulation (R), and Ra...Objective: To evaluate the bioequivalence (BE) of two fixed-dose combination (FDC) formulations of Rosuvastatin and Ezetimibe: Cresadex® EZE 20/10 mg (Abbott Laboratories) as the reference formulation (R), and Racor® Duo 20/10 mg (Laboratorios Leti, S.A.V.) as the test formulation (T). Method: A randomized, single-dose, two-period, two-sequence, open-label, crossover design was employed. Subjects received a single oral dose of either the Test or Reference formulation under fasting conditions, with a 12-day washout period between treatments. Male subjects aged 18 - 45 years with normal health and laboratory values were included. Exclusion criteria encompassed any medical conditions, recent surgery, drug or alcohol use, and hypersensitivity to the study drugs. Blood samples were collected at pre-dose and multiple post-dose time points and analyzed using a validated LC-MS/MS method to quantify Rosuvastatin and Ezetimibe concentrations in plasma. Descriptive statistics were used to summarize pharmacokinetic (PK) parameters. ANOVA was conducted to compare the ln-transformed values of Cmax, AUC0−t, and AUC0−∞. Schuirmann’s two one-sided t-tests were applied to assess bioequivalence (BE). Results: The 90% Confidence Intervals for the ln-transformed ratios of Cmax, AUC0−t, and AUC0−∞ fell within the acceptance range of 80% to 125%, demonstrating bioequivalence between the Test and Reference formulations. Both formulations were well-tolerated, with no serious adverse events reported. Conclusions: The results of this study confirm the bioequivalence of the two tested FDC Rosuvastatin/Ezetimibe formulations: Cresadex® EZE (Abbott Laboratories) and Racor® Duo (Laboratorios Leti, S.A.V.). These findings endorse the therapeutic interchangeability of these products, providing clinicians with greater flexibility in the treatment of hyperlipidemia.展开更多
Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fastin...Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.展开更多
Objectives: To compare the rate and extent of absorption of Racor® 20 mg (Rosuvastatin calcium 20 mg) tablet of Laboratorios Leti, S.A.V., with Crestor® 20 mg (Rosuvastatin calcium 20 mg) tablet of AstraZene...Objectives: To compare the rate and extent of absorption of Racor® 20 mg (Rosuvastatin calcium 20 mg) tablet of Laboratorios Leti, S.A.V., with Crestor® 20 mg (Rosuvastatin calcium 20 mg) tablet of AstraZeneca, UK Limited in healthy adult human subjects under fasting conditions. Method: This was an open label, analyst blind, balanced, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study in healthy, adult, human subjects under fasting condition. Twenty-four (24) subjects were planned as per the protocol and all subjects completed both periods of the study. The concentrations of Rosuvastatin in plasma were quantitated using a validated LC-MS/MS method of analysis and plasma levels were submitted for statistical analysis. Cmax, AUC0-t, AUC0-∞, Tmax, t1/2, Kel (hrs-1), percent AUC extrapolated [100 * (AUC0-∞ - AUC0-t)/AUC0-∞] (AUC_%Extrapobs) were calculated for rosuvastatin in plasma using SAS® version 9.1.3, SAS Institute. Inc. USA.CARY. ANOVA, 90% confidence interval using Schuirmann’s two one-sided test for bioequivalence, power and ratio analysis, for lntransformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ were computed and reported for Rosuvastatin in plasma for BE. Results: Data showed that 90% confidence intervals for the test/reference geometric mean ratios (GMR) of Cmax (95.01 - 112.66), AUC0-t (93.38 - 111.67) and AUC0-∞ (93.65 - 111.29) were within the BE (80% - 125%) acceptance range. Conclusions: Two products formulation, reference (R) Crestor® (rosuvastatin calcium) of AstraZeneca and test (T), Racor® (rosuvastatin calcium) of Laboratorios Leti S.A.V., with a single dose of 20 mg, under fasting conditions were bioequivalent. No severe, serious or unexpected adverse events (AEs) were reported in this study.展开更多
Background: Vonoprazan fumarate, a novel potassium-competitive acid blocker, outperforms traditional proton pump inhibitors in acid suppression and can be effectively combined with antibiotics to eradicate Helicobacte...Background: Vonoprazan fumarate, a novel potassium-competitive acid blocker, outperforms traditional proton pump inhibitors in acid suppression and can be effectively combined with antibiotics to eradicate Helicobacter pylori. Objective: The study aimed to determine if two Vonoprazan formulations—Vonoprazan Fumarate 20 mg Tablet of Beximco Pharmaceuticals Limited, Bangladesh (test product) and Takecab 20 mg Tablet of Takeda Pharmaceutical Company Limited, Japan (reference product)—met FDA’s bioequivalence requirements by comparing their pharmacokinetic characteristics in healthy Bangladeshi adults. Methods: This was a single-center, randomized, open-label, two-period, two-sequence, laboratory-blind, double-crossover experiment. After 10 hours of fasting, 18 subjects were randomly assigned to receive a single oral dose of either formulation. During each treatment period, blood samples were collected at specific times (pre-dose and up to 48 hours post-dose) to measure plasma Vonoprazan levels using liquid chromatography-tandem mass spectrometry. A non-compartmental model was used to calculate pharmacokinetic parameters using the plasma drug concentration-time profile. A statistical comparison of the pharmacokinetic parameters of the two formulations of the test and reference product was conducted using SAS® statistical software to assess the bioequivalence. Primary pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-∞) and secondary parameters (Tmax, T1/2, Kel, and AUC extrapolation) were calculated for both drug formulations. If the confidence intervals for the natural log-transformed Cmax, AUC0-t, and AUC0-∞ values fell between 80% and 125%, the drug products would be considered bioequivalent. Result: The geometric mean ratio of Vonoprazan between the test and reference groups was found to be 109.04% (99.47% - 119.53%), 101.37% (95.58% - 107.50%), and 101.24% (95.43% - 107.41%), with 90% confidence intervals (CIs) for the Cmax, AUC0–t, and AUC0–∞, and these outcomes met the regulatory requirements for assuming bioequivalence. Conclusion: The results demonstrated that the generic formulation of Vonoprazan 20 mg Tablet of Beximco Pharmaceuticals Limited is bioequivalent to the reference product.展开更多
Background: This study aimed to evaluate the bioequivalence of the two formulations of metformin 1000 mg XR tablets in healthy male volunteers under fasting conditions. Methods: This was a randomized, single-dose, ope...Background: This study aimed to evaluate the bioequivalence of the two formulations of metformin 1000 mg XR tablets in healthy male volunteers under fasting conditions. Methods: This was a randomized, single-dose, open-label, two-period, two-sequence, crossover and single-dose study to compare the bioequivalence (BE) profile of Metformin (metformin hydrochloride) 1000 mg XR tablet of Laboratorios Leti S.A.V., with Glucophage® (metformin hydrochloride) 1000 mg XR tablet of Merck Serono GmbH in 26 adult healthy subjects. The pharmacokinetic (PK) parameters Cmax, AUC0−tand AUC0→∞were calculated based on the plasma drug concentration-time profile measured by liquid chromatography-mass spectrometry (LC-MS/MS). The safety was assessed throughout the study. The two formulations test (T) and reference (R) were considered bioequivalent if 90% confidence interval (CI) were within BE acceptance range of 80.00% - 125.00% for Cmax, AUC0−tand AUC0→∞. Results: A total of 25 subjects completed both study periods 90% confidence intervals (CIs) of the test/reference ratios were Cmax: 92.30% (89.08% - 96.97%), AUC0−t: 91.83% (87.11% - 94.11%) and AUC0→∞: 91.83% (87.23% - 94.85%) to metformin 1000 mg extended release. PK parameters were within the accepted bioequivalence criteria. The results show that no significant differences were observed between the pharmacokinetic profiles of the T and R formulations. No serious adverse events were reported in this study. Conclusion: The two formulations of metformin hydrochloride 1000 mg XR were bioequivalent in healthy subjects under fasting conditions.展开更多
In the present study, we determined the pharmacokinetics and bioequivalence of two amlodipine tablets in Chinese male and female volunteers using HPLC-MS/IVIS method. A randomized, two-period and crossover design was ...In the present study, we determined the pharmacokinetics and bioequivalence of two amlodipine tablets in Chinese male and female volunteers using HPLC-MS/IVIS method. A randomized, two-period and crossover design was conducted in 20 healthy volunteers （14 male subjects and six female subjects）. A single dose of either the reference or test formulation was given at the start of each period. Blood samples were collected before drug administration and at 1, 2, 3, 4, 5, 6, 8, I0, 12, 24, 48, 72, 96, 120 and 144 h after drug administration. Plasma amlodipine was detected by HPLC-MS/MS method, and the pharmacokinetic parameters were analyzed using DAS 3.2.8. The developed HPLC-MS/MS method was suitable for the analysis of amlodipine in biological matrix samples. The main pharmacokinetic parameters between the trial preparation and the reference preparation met the regulatory criteria for bioequivalence, and the two preparations were both well tolerated.展开更多
Aim To establish a LC-MS method for determining the concentration of nifedipine in human plasma and to evaluate the pharmacokinetic characteristics of nifedipine sustained-release tablets. Methods A XB-C18 （5 μm, 4....Aim To establish a LC-MS method for determining the concentration of nifedipine in human plasma and to evaluate the pharmacokinetic characteristics of nifedipine sustained-release tablets. Methods A XB-C18 （5 μm, 4.6 mm ×150 mm） column and a mobile phase of methanol： 0.01 mol·L^-1ammonium acetate （60：40, V/V） were used to separate nifedipine, the detections was accuracy under atmosperic pressure electronic spray ionization （AP-ESI） mode and ion mass spectrum （m/z） of 314.9 [M＋H]^＋ for nifedipine, and 320.8 [M＋H]^＋ for lorazepam （Internal Standard, IS）. Results The linear range of nifedipine was 0.3 - 80 ng·mL^-1 （ r = 0.9997）, and the limit of quantitation （LOQ） was 0.3 ng·mL^-1. The nifedipine pharmacokinetic parameters after a single dose of 20 mg nifedipine sustained-release tablets test （T） or reference （R） were as the followings, t1/2 （6.73 ± 2.00） h and （7.04 ± 2.18） h, Tmax （4.28 ± 0.70） h and （4.48 ± 0.70） h, Cmax（39.66 ± 10.58） ng·mL^-1 and （40.19 ± 10.97） ng·mL^-1, AUC0-36 （391.63 ± 108.55） ng·mL^-1·h and （387.57 ± 121.51） ng·mL^-1·h, and AUC0-∞ （408.28 ± 121.16） ng·mL^-1·h and （406.15 ± 133.13） ng·mL^-1·h. The relative bioavailability of nifedipine sustained-release tablets （test） was （103.02 ± 13.93） %. Conclusion LC-MS method for the determination of concentrations of nifedipine in human plasma was sensitive and accurate, and could be used in nifedipine bioavailability and pharmacokinetic studies.展开更多
A rapid and sensitive high performance liquid chromatography-mass spectrometry （HPLC-MS） method for the quantification of nimesulide in human plasma was developed and validated. Sample aliquots of 100μL were extrac...A rapid and sensitive high performance liquid chromatography-mass spectrometry （HPLC-MS） method for the quantification of nimesulide in human plasma was developed and validated. Sample aliquots of 100μL were extracted by one-step liquid-liquid extraction after addition of hydrochlorothiazide as the internal standard （IS）. Analytes were separated on a reverse phase C18 column using methanol-water （84：16, v/v） as the mobile phase and detected by a single quadrupole mass spectrometer in selected ion monitoring （SIM） negative mode. Monitored m/z values for nimesulide and IS were 307.00 and 295.90, respectively. The overall run time was 4.2 min. Validation experiments demonstrated good precision and accuracy over a wide concentration range of 20.0-7000 ng/mL with a lower limit of quantification （LLOQ） at 20.0 ng/mL. No interference by endogenous substances or matrix effect was observed. Average extraction recoveries for nimesulide and IS were all greater than 84.4%. The assay was successfully applied to a bioequivalence study of nimesulide dispersible tablets in Chinese male volunteers after oral administration.展开更多
Aim To evaluate the pharmacokinetics and bioequivalence of domestic pantoprazole sodium enteric-coated tablets as compared with imported pantoprazole enteric-coated tablets. Methods This was an open randomized, two pe...Aim To evaluate the pharmacokinetics and bioequivalence of domestic pantoprazole sodium enteric-coated tablets as compared with imported pantoprazole enteric-coated tablets. Methods This was an open randomized, two periods cross over study on twenty healthy male volunteers. The pantoprazole concentrations in plasma after an oral dose of 40 mg pantoprzaole preparations were determined by a HPLC-UV method. Non-compartmental method was used for the calculation of pharmacokinetic parameters. Logarithm-transformed Cmax and A UC were analyzed by the analysis of variance （ANOVA） with 90% confidence intervals. Results The main pharmacokinetics parameters of domestic pantoprazole sodium enteric-coated tablets and imported pantoprazole sodium enteric-coated tablets were as following： Cmax （3610 ± 956）, （3466 ± 1209） ng·mL^-1, tmax （3.00 ± 0.40）, （3.00 ± 0.46） h, AUC0-t （8140 ± 5065）, （8390 ± 5474） ng·h·mL^-1, AUC0-∞ （8293 ± 5094）, （8625 ± 5606） ng·h·mL^-1, t1/2 （1.61 ± 0.28）, （1.85 ± 0.27） h, respectively. Conclusion Domestic pantoprazole sodium enteric-coated tablets were bioequivalent with the imported pantoprazole sodium enteric-coated tablets.展开更多
Aim To develop a rapid, simple, and sensitive high-performance liquid chromatographic (HPLC) method for the determination of cefprozil in human plasma and to study its pharmacokinetics and bioequivalence after 0.5 g o...Aim To develop a rapid, simple, and sensitive high-performance liquid chromatographic (HPLC) method for the determination of cefprozil in human plasma and to study its pharmacokinetics and bioequivalence after 0.5 g oral doses of cefprozil granules and tablets. Methods The blood concentration of cefprozil was analyzed after extracted with 6% trichloroacetic acid, using tinidazole as internal standard (I.S.). A C_ 18 column was used to separate cefprozil with mobile phase of methanol, purified water and glac...展开更多
Aim To establish a HPLC method for the determination of bicalutamide plasma concentration and to evaluate the bioequivalence of bicalutamide capsules （test） and tablets （reference）. Methods A single oral dose of 5...Aim To establish a HPLC method for the determination of bicalutamide plasma concentration and to evaluate the bioequivalence of bicalutamide capsules （test） and tablets （reference）. Methods A single oral dose of 50 mg bicalutamide capsules or tablets were given to 48 Chinese healthy volunteers in a one period parallel design test. Bicalutamide in plasma was analyzed using a XB-C18 column with a mobile phase of acetonitrile-water （60：40, V/V） and the dectection wavelength of 272 nm and it is pharmacokinetic parameters were calculated and evaluated using DAS2.0. Results The linear range of bicalutamide was 10 - 1200 ng·mL^-1. The main pharmacokinetic parameters of the test and reference were as the followings, t1/2 （138.36 ± 32.03） and （146.12 ± 27.04） h, Tmax （17.17 ± 4.65） and （16.92 ± 4.85） h, Cmax（910.83 ± 130.49） and （868.71 ± 115.35） ng·mL^-1 AUC0-672（172437.08 ± 3986.07） and （176842.34 ± 35733.85） ng·mL^-1·h, and AUC0-∞ （179456.55 ± 43127.65） and （185270.39 ± 39688.63） ng·mL^-1·h, respectively. The two-one side t-test analysis showed that the confidence intervals of Crux, A UC0-672 and A UC0-∞ were （98.9% - 100.7%）, （98.8% - 100.6%） and （99.7% - 101.7%）, respectively. Conclusion The relative bioavailability of bicalutamide capsules was 97.51%. The bioequivalence was demonstrated by the two-one side t-test展开更多
The clinical pharmacokinetics of osmotic pump controlled release tablets of terazosin hydrochloride in healthy volunteers was studied.A sensitive and rapid HPLC method was used to determine the terazosin plasma concen...The clinical pharmacokinetics of osmotic pump controlled release tablets of terazosin hydrochloride in healthy volunteers was studied.A sensitive and rapid HPLC method was used to determine the terazosin plasma concentrations,and single and multiple doses of terazosin hydrochloride regular tablets（reference tablets）and osmotic pump controlled release tablets were orally administrated in randomized crossover design.The results showed that the C_（max）of the reference tablets after single oral dose（（120.56±23.15）ng/mL）in 20 healthy volunteers was significantly higher than that of controlled release tablets （（95.27±16.35）ng/mL）.The T_（max）of the controlled release tablets（（2.65±0.82）h）was significantly longer than that of reference tablets（（1.27±0.61）h）（P0.05）.The relative bioavailability of the controlled release tablets was found to be（105.85±6.12）%. The multiple oral dose pharmacokinetic parameters of the regular tablets and controlled release tablets were as follows：AUC_（SS） were（1275.17±175.35）and（1382.65±205.31）ng·h/mL respectively,C_（max）were（128.15±22.37）and（98.57±18.16）ng/mL respectively,T_（max）were（1.35±0.71）and（2.76±0.85）h respectively,C_（av）were（53.13±9.12）and（57.61±9.25）ng/mL respectively, and DF were（2.25±0.26）%and（1.62±0.25）%respectively.The relative bioavailability of the controlled release tablets to the reference tablets was（108.43±6.26）%.The controlled release tablet of terazosin hydrochloride was bioequivalent to the reference tablet.The controlled release tablet exhibited a sustained-release property with a significantly longer T_（max）and lower C_（max）.展开更多
Recently,generic drug products have played an increasingly important role in the health care system globally,especially in the developing world,as they provide for an effective and more affordable alternative for heal...Recently,generic drug products have played an increasingly important role in the health care system globally,especially in the developing world,as they provide for an effective and more affordable alternative for healthcare professionals.Generic drug products are proven therapeutically equivalent to the corresponding innovator’s product,and hence can be substituted in clinical practice.The objective of generic drug development is to develop a stable and bioequivalent generic drug product with desirable properties in a timely manner.This presentation is intended to summarize three important sequential stages essential for successful generic drug development based on a regulatory experience in reviewing and evaluating the Pharmaceutical Development Section(P2)of the ASEAN Common Technical Dossier(ACTD)of generic drug product applications submitted to the Food and Drug Administration,Thailand[1,2].展开更多
A highly sensitive, rapid and rugged liquid chromatography-tandem mass spectrometw （LC-ESI-MS/MS） method was developed for reliable estimation of amantadine （AMD）, an antiviral drug in human plasma. The analyte an...A highly sensitive, rapid and rugged liquid chromatography-tandem mass spectrometw （LC-ESI-MS/MS） method was developed for reliable estimation of amantadine （AMD）, an antiviral drug in human plasma. The analyte and internal standard （IS）, amantadine-d6 （AMD-d6）, were extracted from 200μL plasma by solid phase extraction on Phenomenex Strata-X-C 33 ~t cartridges. Chromatography was performed on Synergi^TM Hydro-RP C18 （150 mm×4.6 mm, 4 μm） analytical column using a mixture of acetonitrile and 10 mM ammonium formate, pH 3.0 （80：20, v/v） as the mobile phase. Detection and quantitation was done by multiple reaction monitoring in the positive ionization mode for AMD （m/z 152.1→ 135.1 ） and IS （m/z 158.0 → 141.1） on a triple quadrupole mass spectrometer. The assay was linear in the concentration range of 0.50-500 ng/mL with correlation coefficient （r^2） 〉 0.9969. The limit of detection of the method was 0.18 ng/mL The intra-batch and inter-batch precisions were 〈 5.42% and the accuracy varied from 98.47% to 105.72%. The extraction recovery of amantadine was precise and quantitative in the range of 97.89%-100.28%. IS-normalized matrix factors for amantadine varied from 0.981 to 1.012. The stability of AMD in whole blood and plasma was evaluated under different conditions. The developed method was successfully applied for a bioequivalence study with 100 mg of AMD in 32 healthy volunteers. The reproducibility of the assay was determined by reanalysis of 134 subject samples.展开更多
Obesity can be considered as a chronic illness of epidemic proportion and its incidents have increased exponentially in recent years.The use of anti-obesity drugs such as sibutramine is somewhat helpful.There is a nee...Obesity can be considered as a chronic illness of epidemic proportion and its incidents have increased exponentially in recent years.The use of anti-obesity drugs such as sibutramine is somewhat helpful.There is a need to quantify such drugs in biological samples,which is generally quite difficult.In this report,we developed and validated a simple,sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of sibutramine (SB) and its two metabolites N-des methyl sibutramine (DSB) and N-di desmethyl sibutramine (DDSB) in human plasma.Zorbax SBC18 (4.6 mm × 75 mm,3.5 μm,80 (A)) analytical column and 5 mM ammonium formate:acetonitrile (10∶90,v/v) mobile phase were used for chromatographic separation of SB,DSB and DDSB.Multiple reaction monitoring (MRM) in the positive mode was used to detect SB,DSB and DDSB at m/z 280.3/124.9,266.3/125.3 and 252.2/124.9,respectively.Liquid liquid extraction was used for the extraction of analytes and internal standard from human plasma.This method was validated over a linear concentration range of 10.0-10,000.0 pg/mL for SB,DSB and DDSB with correlation coefficients (r) of ≥0.9997.The drug and the two metabolites were stable in plasma samples.The validated method was successfully applied in a bioequivalence and pharmacokinetic study with human volunteers under fasting condition.展开更多
A sensitive and selective method has been proposed for the simultaneous determination of amlodipine(AML),valsartan(VAL) and hydrochlorothiazide(HCTZ) in human plasma by liquid chromatography–tandem mass spectrometry...A sensitive and selective method has been proposed for the simultaneous determination of amlodipine(AML),valsartan(VAL) and hydrochlorothiazide(HCTZ) in human plasma by liquid chromatography–tandem mass spectrometry(LC–MS/MS). The analytes and their deuterated analogs were quantitatively extracted from100 μL human plasma by solid phase extraction on Oasis HLB cartridges. The chromatographic separation of the analytes was achieved on a Chromolith RP18 e(100 mm × 4.6 mm) analytical column within 2.5 min. The resolution factor between AML and VAL, AML and HCTZ, and VAL and HCTZ was 2.9, 1.5 and 1.4, respectively,under isocratic conditions. The method was validated over a dynamic concentration range of 0.02–20.0 ng/m L for AML, 5.00–10,000 ng/m L for VAL and 0.20–200 ng/m L for HCTZ. Ion-suppression/enhancement effects were investigated by post-column infusion technique. The mean IS-normalized matrix factors for AML, VAL and HCTZ were 0.992, 0.994 and 0.998, respectively. The intra-batch and inter-batch precision(% CV) across quality control levels was ≤ 5.56% and the recovery was in the range of 93.4%–99.6% for all the analytes. The method was successfully applied to a bioequivalence study of 5 mg AML + 160 mg VAL + 12.5 mg HCTZ tablet formulation(test and reference) in 18 healthy Indian males under fasting. The mean log-transformed ratios of C max, AUC0–120 h and AUC0-inf and their 90% CIs were within 90.2%–102.1%. The assay reproducibility was demonstrated by reanalysis of 90 incurred samples.展开更多
Bioequivalence(BE) assessment of topical dermatological products is a long standing challenge. The development of generic topical dermatological products has often been hampered due to the limited number of acceptable...Bioequivalence(BE) assessment of topical dermatological products is a long standing challenge. The development of generic topical dermatological products has often been hampered due to the limited number of acceptable approaches, which are capable of determining the BE between generic products and reference list products. The aim of this manuscript is to review different BE assessment approaches of topical dermatological products. Besides, the advances in BE evaluation and biowaivers are also provided. Currently, except in the case of dermatological corticosteroids, the golden rule to establish the BE of most topical dermatological products still heavily relied on clinical endpoint trials,which are often unreliable, time-consuming and expensive. The regulatory agencies and pharmaceutical industries are forging ahead to the development of new surrogate BE assessment approaches for other topical dermatological products. These promising approaches include dermatopharmacokinetic study(DPK), dermal microdialysis(DMD), in vitro studies, pharmacokinetic study(PK), near-infrared spectrometry(NIR), and confocal Raman spectroscopy(CRS). In addition, the expansion of biowaivers for topical dermatological products has been explored by pharmaceutical scientists. In conclusion, to accelerate the development and approval of topical dermatological products, emphasis should be put on the following areas, i.e., optimizing and standardizing the existing BE assessment methods, exploring novel alternatives of BE assessment approaches, and expanding biowaivers for topical dermatological products.展开更多
The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dis...The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions(ASDs)capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study.In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions(ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration(Cmax), and the time(Tmax) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval(CI) for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the reference drug exceeded the acceptable bioequivalence(BE) limits(0.80–1.25). However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit,calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.展开更多
文摘Aim To evaluate the bioequivalence of two brands of losartan/hydrochlorothiazide （50 mg/12.5 mg） compound tablets in healthy Chinese male volunteers. Methods An open, randomized, single-dose, two-period cross-over study with a wash-out period of 7 d was conducted. Twenty healthy male volunteers were given a single dose 50 mg losartan/12.5 mg hydrochlorothiazide of either test （T） or reference （R） compound tablets, respectively. Blood samples were collected up to 48 h after oral administration. The concentrations of losartan and hydrochlorothiazide in plasma were determined by a validated HPLC-ESI-MS method. Results In the case of losartan, the 90% confidence intervals of two one-side test for percent ratios with a significant level （α） of 0. 05 were 86% - 112% for AUC0-12 and 89% - 134% for Cmax, respectively, which were within the interval proposed in the Chinese Pharmacopoeia, 80% - 125% of AUC and 70% - 143% of Cmax, respectively. Similarly, the 90% confidence intervals for percent ratios were 85% - 100% and 75% - 102% for hydrochlorothiazide, both of which fell into the accepted interval. Conclusion Two immediate-release compound tablets of losartan/hydrochlorothiazide are bioequivalent from a statistical standpoint in the extent and rate of absorption from the single-dose study in healthy Chinese male volunteers.
文摘Background: Dienogest is a potential treatment for pelvic pain associated with endometriosis, a condition of significant concern in gynaecology. The current study was conducted as a crossover-randomized bioequivalence assessment of two oral Dienogest 2 mg formulations, aiming to provide valuable insights for healthcare professionals and researchers in this field. Objective: The primary aim of this research was to evaluate and compare the pharmacokinetic characteristics of Dienogest 2 mg tablets. Dinogest (Dienogest 2 mg) tablets, manufactured by Nuvista Pharma Limited in Bangladesh, and Visanne (Dienogest 2 mg) tablets, manufactured by Bayer Pharma in Germany, were the test and reference formulations, respectively. Materials and Method: The study was an open-label, balanced, randomized, two treatments, two sequences, two periods, two-way crossover, laboratory blind, single oral dose bioequivalence study conducted in healthy adult females under fasting conditions. The study was carried out on 13 healthy, non-pregnant female subjects, and all the subjects completed both study periods with a 15-day washout in between. Randomization was used to assign the test and reference formulations to the subjects. Following each oral administration, a series of blood samples were obtained at different time intervals from pre-dose to 72 hours post-dose and analyzed for Dienogest concentrations using a validated bio-analytical method. A standard non-compartmental model was used to analyze the pharmacokinetic parameters. The primary pharmacokinetic parameters were peak plasma drug concentration (C<sub>max</sub>), the area under the plasma concentration-time curve from time zero to time t (AUC<sub>0–t</sub>), and AUC from t = 0 to infinity (AUC<sub>0–∞</sub>). The other PK parameters included time to reach C<sub>max</sub> (T<sub>max</sub>), terminal elimination rate constant (K<sub>el</sub>), and half-life (t<sub>1/2</sub>). Result: The ratios and 90% CI for the geometric mean test/reference were 95.53% (86.70% - 105.26%) for C<sub>max</sub>, 101.75% (95.42% - 108.49%) for AUC<sub>0</sub><sub>−</sub><sub>t</sub>, and 101.54% (95.59%% - 107.87%) for AUC<sub>0</sub><sub>−</sub><sub>∞</sub>. The formulations were bioequivalent since the 90% CIs for the geometric mean test/reference ratios were 80% to 125%, according to the predetermined range of US Food and Drug Administration (FDA) requirements. Conclusion: This single-dose investigation shows that the Dienogest test and reference formulations exhibited a rate and degree of absorption that met the regulatory requirements for bioequivalence.
文摘Objective: To evaluate the bioequivalence (BE) of two fixed-dose combination (FDC) formulations of Rosuvastatin and Ezetimibe: Cresadex® EZE 20/10 mg (Abbott Laboratories) as the reference formulation (R), and Racor® Duo 20/10 mg (Laboratorios Leti, S.A.V.) as the test formulation (T). Method: A randomized, single-dose, two-period, two-sequence, open-label, crossover design was employed. Subjects received a single oral dose of either the Test or Reference formulation under fasting conditions, with a 12-day washout period between treatments. Male subjects aged 18 - 45 years with normal health and laboratory values were included. Exclusion criteria encompassed any medical conditions, recent surgery, drug or alcohol use, and hypersensitivity to the study drugs. Blood samples were collected at pre-dose and multiple post-dose time points and analyzed using a validated LC-MS/MS method to quantify Rosuvastatin and Ezetimibe concentrations in plasma. Descriptive statistics were used to summarize pharmacokinetic (PK) parameters. ANOVA was conducted to compare the ln-transformed values of Cmax, AUC0−t, and AUC0−∞. Schuirmann’s two one-sided t-tests were applied to assess bioequivalence (BE). Results: The 90% Confidence Intervals for the ln-transformed ratios of Cmax, AUC0−t, and AUC0−∞ fell within the acceptance range of 80% to 125%, demonstrating bioequivalence between the Test and Reference formulations. Both formulations were well-tolerated, with no serious adverse events reported. Conclusions: The results of this study confirm the bioequivalence of the two tested FDC Rosuvastatin/Ezetimibe formulations: Cresadex® EZE (Abbott Laboratories) and Racor® Duo (Laboratorios Leti, S.A.V.). These findings endorse the therapeutic interchangeability of these products, providing clinicians with greater flexibility in the treatment of hyperlipidemia.
文摘Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.
文摘Objectives: To compare the rate and extent of absorption of Racor® 20 mg (Rosuvastatin calcium 20 mg) tablet of Laboratorios Leti, S.A.V., with Crestor® 20 mg (Rosuvastatin calcium 20 mg) tablet of AstraZeneca, UK Limited in healthy adult human subjects under fasting conditions. Method: This was an open label, analyst blind, balanced, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study in healthy, adult, human subjects under fasting condition. Twenty-four (24) subjects were planned as per the protocol and all subjects completed both periods of the study. The concentrations of Rosuvastatin in plasma were quantitated using a validated LC-MS/MS method of analysis and plasma levels were submitted for statistical analysis. Cmax, AUC0-t, AUC0-∞, Tmax, t1/2, Kel (hrs-1), percent AUC extrapolated [100 * (AUC0-∞ - AUC0-t)/AUC0-∞] (AUC_%Extrapobs) were calculated for rosuvastatin in plasma using SAS® version 9.1.3, SAS Institute. Inc. USA.CARY. ANOVA, 90% confidence interval using Schuirmann’s two one-sided test for bioequivalence, power and ratio analysis, for lntransformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ were computed and reported for Rosuvastatin in plasma for BE. Results: Data showed that 90% confidence intervals for the test/reference geometric mean ratios (GMR) of Cmax (95.01 - 112.66), AUC0-t (93.38 - 111.67) and AUC0-∞ (93.65 - 111.29) were within the BE (80% - 125%) acceptance range. Conclusions: Two products formulation, reference (R) Crestor® (rosuvastatin calcium) of AstraZeneca and test (T), Racor® (rosuvastatin calcium) of Laboratorios Leti S.A.V., with a single dose of 20 mg, under fasting conditions were bioequivalent. No severe, serious or unexpected adverse events (AEs) were reported in this study.
文摘Background: Vonoprazan fumarate, a novel potassium-competitive acid blocker, outperforms traditional proton pump inhibitors in acid suppression and can be effectively combined with antibiotics to eradicate Helicobacter pylori. Objective: The study aimed to determine if two Vonoprazan formulations—Vonoprazan Fumarate 20 mg Tablet of Beximco Pharmaceuticals Limited, Bangladesh (test product) and Takecab 20 mg Tablet of Takeda Pharmaceutical Company Limited, Japan (reference product)—met FDA’s bioequivalence requirements by comparing their pharmacokinetic characteristics in healthy Bangladeshi adults. Methods: This was a single-center, randomized, open-label, two-period, two-sequence, laboratory-blind, double-crossover experiment. After 10 hours of fasting, 18 subjects were randomly assigned to receive a single oral dose of either formulation. During each treatment period, blood samples were collected at specific times (pre-dose and up to 48 hours post-dose) to measure plasma Vonoprazan levels using liquid chromatography-tandem mass spectrometry. A non-compartmental model was used to calculate pharmacokinetic parameters using the plasma drug concentration-time profile. A statistical comparison of the pharmacokinetic parameters of the two formulations of the test and reference product was conducted using SAS® statistical software to assess the bioequivalence. Primary pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-∞) and secondary parameters (Tmax, T1/2, Kel, and AUC extrapolation) were calculated for both drug formulations. If the confidence intervals for the natural log-transformed Cmax, AUC0-t, and AUC0-∞ values fell between 80% and 125%, the drug products would be considered bioequivalent. Result: The geometric mean ratio of Vonoprazan between the test and reference groups was found to be 109.04% (99.47% - 119.53%), 101.37% (95.58% - 107.50%), and 101.24% (95.43% - 107.41%), with 90% confidence intervals (CIs) for the Cmax, AUC0–t, and AUC0–∞, and these outcomes met the regulatory requirements for assuming bioequivalence. Conclusion: The results demonstrated that the generic formulation of Vonoprazan 20 mg Tablet of Beximco Pharmaceuticals Limited is bioequivalent to the reference product.
文摘Background: This study aimed to evaluate the bioequivalence of the two formulations of metformin 1000 mg XR tablets in healthy male volunteers under fasting conditions. Methods: This was a randomized, single-dose, open-label, two-period, two-sequence, crossover and single-dose study to compare the bioequivalence (BE) profile of Metformin (metformin hydrochloride) 1000 mg XR tablet of Laboratorios Leti S.A.V., with Glucophage® (metformin hydrochloride) 1000 mg XR tablet of Merck Serono GmbH in 26 adult healthy subjects. The pharmacokinetic (PK) parameters Cmax, AUC0−tand AUC0→∞were calculated based on the plasma drug concentration-time profile measured by liquid chromatography-mass spectrometry (LC-MS/MS). The safety was assessed throughout the study. The two formulations test (T) and reference (R) were considered bioequivalent if 90% confidence interval (CI) were within BE acceptance range of 80.00% - 125.00% for Cmax, AUC0−tand AUC0→∞. Results: A total of 25 subjects completed both study periods 90% confidence intervals (CIs) of the test/reference ratios were Cmax: 92.30% (89.08% - 96.97%), AUC0−t: 91.83% (87.11% - 94.11%) and AUC0→∞: 91.83% (87.23% - 94.85%) to metformin 1000 mg extended release. PK parameters were within the accepted bioequivalence criteria. The results show that no significant differences were observed between the pharmacokinetic profiles of the T and R formulations. No serious adverse events were reported in this study. Conclusion: The two formulations of metformin hydrochloride 1000 mg XR were bioequivalent in healthy subjects under fasting conditions.
基金supported by Institute of Clinical Pharmacy,Central South University,Changsha,China
文摘In the present study, we determined the pharmacokinetics and bioequivalence of two amlodipine tablets in Chinese male and female volunteers using HPLC-MS/IVIS method. A randomized, two-period and crossover design was conducted in 20 healthy volunteers （14 male subjects and six female subjects）. A single dose of either the reference or test formulation was given at the start of each period. Blood samples were collected before drug administration and at 1, 2, 3, 4, 5, 6, 8, I0, 12, 24, 48, 72, 96, 120 and 144 h after drug administration. Plasma amlodipine was detected by HPLC-MS/MS method, and the pharmacokinetic parameters were analyzed using DAS 3.2.8. The developed HPLC-MS/MS method was suitable for the analysis of amlodipine in biological matrix samples. The main pharmacokinetic parameters between the trial preparation and the reference preparation met the regulatory criteria for bioequivalence, and the two preparations were both well tolerated.
文摘Aim To establish a LC-MS method for determining the concentration of nifedipine in human plasma and to evaluate the pharmacokinetic characteristics of nifedipine sustained-release tablets. Methods A XB-C18 （5 μm, 4.6 mm ×150 mm） column and a mobile phase of methanol： 0.01 mol·L^-1ammonium acetate （60：40, V/V） were used to separate nifedipine, the detections was accuracy under atmosperic pressure electronic spray ionization （AP-ESI） mode and ion mass spectrum （m/z） of 314.9 [M＋H]^＋ for nifedipine, and 320.8 [M＋H]^＋ for lorazepam （Internal Standard, IS）. Results The linear range of nifedipine was 0.3 - 80 ng·mL^-1 （ r = 0.9997）, and the limit of quantitation （LOQ） was 0.3 ng·mL^-1. The nifedipine pharmacokinetic parameters after a single dose of 20 mg nifedipine sustained-release tablets test （T） or reference （R） were as the followings, t1/2 （6.73 ± 2.00） h and （7.04 ± 2.18） h, Tmax （4.28 ± 0.70） h and （4.48 ± 0.70） h, Cmax（39.66 ± 10.58） ng·mL^-1 and （40.19 ± 10.97） ng·mL^-1, AUC0-36 （391.63 ± 108.55） ng·mL^-1·h and （387.57 ± 121.51） ng·mL^-1·h, and AUC0-∞ （408.28 ± 121.16） ng·mL^-1·h and （406.15 ± 133.13） ng·mL^-1·h. The relative bioavailability of nifedipine sustained-release tablets （test） was （103.02 ± 13.93） %. Conclusion LC-MS method for the determination of concentrations of nifedipine in human plasma was sensitive and accurate, and could be used in nifedipine bioavailability and pharmacokinetic studies.
文摘A rapid and sensitive high performance liquid chromatography-mass spectrometry （HPLC-MS） method for the quantification of nimesulide in human plasma was developed and validated. Sample aliquots of 100μL were extracted by one-step liquid-liquid extraction after addition of hydrochlorothiazide as the internal standard （IS）. Analytes were separated on a reverse phase C18 column using methanol-water （84：16, v/v） as the mobile phase and detected by a single quadrupole mass spectrometer in selected ion monitoring （SIM） negative mode. Monitored m/z values for nimesulide and IS were 307.00 and 295.90, respectively. The overall run time was 4.2 min. Validation experiments demonstrated good precision and accuracy over a wide concentration range of 20.0-7000 ng/mL with a lower limit of quantification （LLOQ） at 20.0 ng/mL. No interference by endogenous substances or matrix effect was observed. Average extraction recoveries for nimesulide and IS were all greater than 84.4%. The assay was successfully applied to a bioequivalence study of nimesulide dispersible tablets in Chinese male volunteers after oral administration.
文摘Aim To evaluate the pharmacokinetics and bioequivalence of domestic pantoprazole sodium enteric-coated tablets as compared with imported pantoprazole enteric-coated tablets. Methods This was an open randomized, two periods cross over study on twenty healthy male volunteers. The pantoprazole concentrations in plasma after an oral dose of 40 mg pantoprzaole preparations were determined by a HPLC-UV method. Non-compartmental method was used for the calculation of pharmacokinetic parameters. Logarithm-transformed Cmax and A UC were analyzed by the analysis of variance （ANOVA） with 90% confidence intervals. Results The main pharmacokinetics parameters of domestic pantoprazole sodium enteric-coated tablets and imported pantoprazole sodium enteric-coated tablets were as following： Cmax （3610 ± 956）, （3466 ± 1209） ng·mL^-1, tmax （3.00 ± 0.40）, （3.00 ± 0.46） h, AUC0-t （8140 ± 5065）, （8390 ± 5474） ng·h·mL^-1, AUC0-∞ （8293 ± 5094）, （8625 ± 5606） ng·h·mL^-1, t1/2 （1.61 ± 0.28）, （1.85 ± 0.27） h, respectively. Conclusion Domestic pantoprazole sodium enteric-coated tablets were bioequivalent with the imported pantoprazole sodium enteric-coated tablets.
文摘Aim To develop a rapid, simple, and sensitive high-performance liquid chromatographic (HPLC) method for the determination of cefprozil in human plasma and to study its pharmacokinetics and bioequivalence after 0.5 g oral doses of cefprozil granules and tablets. Methods The blood concentration of cefprozil was analyzed after extracted with 6% trichloroacetic acid, using tinidazole as internal standard (I.S.). A C_ 18 column was used to separate cefprozil with mobile phase of methanol, purified water and glac...
文摘Aim To establish a HPLC method for the determination of bicalutamide plasma concentration and to evaluate the bioequivalence of bicalutamide capsules （test） and tablets （reference）. Methods A single oral dose of 50 mg bicalutamide capsules or tablets were given to 48 Chinese healthy volunteers in a one period parallel design test. Bicalutamide in plasma was analyzed using a XB-C18 column with a mobile phase of acetonitrile-water （60：40, V/V） and the dectection wavelength of 272 nm and it is pharmacokinetic parameters were calculated and evaluated using DAS2.0. Results The linear range of bicalutamide was 10 - 1200 ng·mL^-1. The main pharmacokinetic parameters of the test and reference were as the followings, t1/2 （138.36 ± 32.03） and （146.12 ± 27.04） h, Tmax （17.17 ± 4.65） and （16.92 ± 4.85） h, Cmax（910.83 ± 130.49） and （868.71 ± 115.35） ng·mL^-1 AUC0-672（172437.08 ± 3986.07） and （176842.34 ± 35733.85） ng·mL^-1·h, and AUC0-∞ （179456.55 ± 43127.65） and （185270.39 ± 39688.63） ng·mL^-1·h, respectively. The two-one side t-test analysis showed that the confidence intervals of Crux, A UC0-672 and A UC0-∞ were （98.9% - 100.7%）, （98.8% - 100.6%） and （99.7% - 101.7%）, respectively. Conclusion The relative bioavailability of bicalutamide capsules was 97.51%. The bioequivalence was demonstrated by the two-one side t-test
文摘The clinical pharmacokinetics of osmotic pump controlled release tablets of terazosin hydrochloride in healthy volunteers was studied.A sensitive and rapid HPLC method was used to determine the terazosin plasma concentrations,and single and multiple doses of terazosin hydrochloride regular tablets（reference tablets）and osmotic pump controlled release tablets were orally administrated in randomized crossover design.The results showed that the C_（max）of the reference tablets after single oral dose（（120.56±23.15）ng/mL）in 20 healthy volunteers was significantly higher than that of controlled release tablets （（95.27±16.35）ng/mL）.The T_（max）of the controlled release tablets（（2.65±0.82）h）was significantly longer than that of reference tablets（（1.27±0.61）h）（P0.05）.The relative bioavailability of the controlled release tablets was found to be（105.85±6.12）%. The multiple oral dose pharmacokinetic parameters of the regular tablets and controlled release tablets were as follows：AUC_（SS） were（1275.17±175.35）and（1382.65±205.31）ng·h/mL respectively,C_（max）were（128.15±22.37）and（98.57±18.16）ng/mL respectively,T_（max）were（1.35±0.71）and（2.76±0.85）h respectively,C_（av）were（53.13±9.12）and（57.61±9.25）ng/mL respectively, and DF were（2.25±0.26）%and（1.62±0.25）%respectively.The relative bioavailability of the controlled release tablets to the reference tablets was（108.43±6.26）%.The controlled release tablet of terazosin hydrochloride was bioequivalent to the reference tablet.The controlled release tablet exhibited a sustained-release property with a significantly longer T_（max）and lower C_（max）.
文摘Recently,generic drug products have played an increasingly important role in the health care system globally,especially in the developing world,as they provide for an effective and more affordable alternative for healthcare professionals.Generic drug products are proven therapeutically equivalent to the corresponding innovator’s product,and hence can be substituted in clinical practice.The objective of generic drug development is to develop a stable and bioequivalent generic drug product with desirable properties in a timely manner.This presentation is intended to summarize three important sequential stages essential for successful generic drug development based on a regulatory experience in reviewing and evaluating the Pharmaceutical Development Section(P2)of the ASEAN Common Technical Dossier(ACTD)of generic drug product applications submitted to the Food and Drug Administration,Thailand[1,2].
文摘A highly sensitive, rapid and rugged liquid chromatography-tandem mass spectrometw （LC-ESI-MS/MS） method was developed for reliable estimation of amantadine （AMD）, an antiviral drug in human plasma. The analyte and internal standard （IS）, amantadine-d6 （AMD-d6）, were extracted from 200μL plasma by solid phase extraction on Phenomenex Strata-X-C 33 ~t cartridges. Chromatography was performed on Synergi^TM Hydro-RP C18 （150 mm×4.6 mm, 4 μm） analytical column using a mixture of acetonitrile and 10 mM ammonium formate, pH 3.0 （80：20, v/v） as the mobile phase. Detection and quantitation was done by multiple reaction monitoring in the positive ionization mode for AMD （m/z 152.1→ 135.1 ） and IS （m/z 158.0 → 141.1） on a triple quadrupole mass spectrometer. The assay was linear in the concentration range of 0.50-500 ng/mL with correlation coefficient （r^2） 〉 0.9969. The limit of detection of the method was 0.18 ng/mL The intra-batch and inter-batch precisions were 〈 5.42% and the accuracy varied from 98.47% to 105.72%. The extraction recovery of amantadine was precise and quantitative in the range of 97.89%-100.28%. IS-normalized matrix factors for amantadine varied from 0.981 to 1.012. The stability of AMD in whole blood and plasma was evaluated under different conditions. The developed method was successfully applied for a bioequivalence study with 100 mg of AMD in 32 healthy volunteers. The reproducibility of the assay was determined by reanalysis of 134 subject samples.
文摘Obesity can be considered as a chronic illness of epidemic proportion and its incidents have increased exponentially in recent years.The use of anti-obesity drugs such as sibutramine is somewhat helpful.There is a need to quantify such drugs in biological samples,which is generally quite difficult.In this report,we developed and validated a simple,sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of sibutramine (SB) and its two metabolites N-des methyl sibutramine (DSB) and N-di desmethyl sibutramine (DDSB) in human plasma.Zorbax SBC18 (4.6 mm × 75 mm,3.5 μm,80 (A)) analytical column and 5 mM ammonium formate:acetonitrile (10∶90,v/v) mobile phase were used for chromatographic separation of SB,DSB and DDSB.Multiple reaction monitoring (MRM) in the positive mode was used to detect SB,DSB and DDSB at m/z 280.3/124.9,266.3/125.3 and 252.2/124.9,respectively.Liquid liquid extraction was used for the extraction of analytes and internal standard from human plasma.This method was validated over a linear concentration range of 10.0-10,000.0 pg/mL for SB,DSB and DDSB with correlation coefficients (r) of ≥0.9997.The drug and the two metabolites were stable in plasma samples.The validated method was successfully applied in a bioequivalence and pharmacokinetic study with human volunteers under fasting condition.
文摘A sensitive and selective method has been proposed for the simultaneous determination of amlodipine(AML),valsartan(VAL) and hydrochlorothiazide(HCTZ) in human plasma by liquid chromatography–tandem mass spectrometry(LC–MS/MS). The analytes and their deuterated analogs were quantitatively extracted from100 μL human plasma by solid phase extraction on Oasis HLB cartridges. The chromatographic separation of the analytes was achieved on a Chromolith RP18 e(100 mm × 4.6 mm) analytical column within 2.5 min. The resolution factor between AML and VAL, AML and HCTZ, and VAL and HCTZ was 2.9, 1.5 and 1.4, respectively,under isocratic conditions. The method was validated over a dynamic concentration range of 0.02–20.0 ng/m L for AML, 5.00–10,000 ng/m L for VAL and 0.20–200 ng/m L for HCTZ. Ion-suppression/enhancement effects were investigated by post-column infusion technique. The mean IS-normalized matrix factors for AML, VAL and HCTZ were 0.992, 0.994 and 0.998, respectively. The intra-batch and inter-batch precision(% CV) across quality control levels was ≤ 5.56% and the recovery was in the range of 93.4%–99.6% for all the analytes. The method was successfully applied to a bioequivalence study of 5 mg AML + 160 mg VAL + 12.5 mg HCTZ tablet formulation(test and reference) in 18 healthy Indian males under fasting. The mean log-transformed ratios of C max, AUC0–120 h and AUC0-inf and their 90% CIs were within 90.2%–102.1%. The assay reproducibility was demonstrated by reanalysis of 90 incurred samples.
文摘Bioequivalence(BE) assessment of topical dermatological products is a long standing challenge. The development of generic topical dermatological products has often been hampered due to the limited number of acceptable approaches, which are capable of determining the BE between generic products and reference list products. The aim of this manuscript is to review different BE assessment approaches of topical dermatological products. Besides, the advances in BE evaluation and biowaivers are also provided. Currently, except in the case of dermatological corticosteroids, the golden rule to establish the BE of most topical dermatological products still heavily relied on clinical endpoint trials,which are often unreliable, time-consuming and expensive. The regulatory agencies and pharmaceutical industries are forging ahead to the development of new surrogate BE assessment approaches for other topical dermatological products. These promising approaches include dermatopharmacokinetic study(DPK), dermal microdialysis(DMD), in vitro studies, pharmacokinetic study(PK), near-infrared spectrometry(NIR), and confocal Raman spectroscopy(CRS). In addition, the expansion of biowaivers for topical dermatological products has been explored by pharmaceutical scientists. In conclusion, to accelerate the development and approval of topical dermatological products, emphasis should be put on the following areas, i.e., optimizing and standardizing the existing BE assessment methods, exploring novel alternatives of BE assessment approaches, and expanding biowaivers for topical dermatological products.
基金the National Natural Science Foundation of China (No. 81173009)the Technology Bureau in Shenyang (No. ZCJJ2013402)the Project for New Century Excellent Talents of Ministry of Education (No. NCET-12-1015)
文摘The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions(ASDs)capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study.In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions(ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration(Cmax), and the time(Tmax) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval(CI) for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the reference drug exceeded the acceptable bioequivalence(BE) limits(0.80–1.25). However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit,calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.
