Bioequivalence evaluation of three different oral formulations of ciprofloxacin in healthy volunteers.

Two bioequivalence studies were performed in twenty four healthy male volunteers with the objective of comparing the bioavailability of three different oral formulations of ciprofloxacin as immediate release tablets 250, 500 and 750 mg (test formulations) with a reference formulation at 500 and 750 mg strengths forms. In study 1, the subjects were enrolled in a single-dose, open-label, 3-period, crossover randomised study, designed to compare the bioavailability of two test formulations of ciprofloxacin (A and B) as 250 and 500 mg tablets, compared to the reference formulation (C), as 500 mg tablets. In study 2, the same 24-subjects were included in a single-dose, open-label, 2-period, crossover randomised study, designed to compare the bioavailability of one test formulation of ciprofloxacin (A) as compared to the reference formulation (B), both products as 750 mg tablets. In both studies multiple blood samples were collected over 24 hours post-dosing. One washout period of six days was observed between the periods. Plasma was harvested and assayed for ciprofloxacin using a selective and sensitive high-performance liquid chromatography (HPLC) method with UV detection. The pharmacokinetic parameter values of Cmax and tmax were obtained directly from plasma data, ke was estimated by log-linear regression, and AUC was calculated by trapezoidal rule. Different statistical tests were performed on the basis of untransformed and log-transformed data and the overall residual variance from ANOVA. Assuming the accepted tolerance intervals, a beta-error of 20% and 90% confidence intervals (alpha = 0.10) of all the generally accepted tests (Westlake, Schuirmann test and Wilcoxon-Tukey nonparametric tests) showed that the formulations can be considered as bioequivalent with respect to the extent of absorption, given by the AUC0-infinity and with respect to rate of absorption as assessed by Cmax and tmax.     

Bioequivalence of different prednisolone tablet formulations

The relative bioavailability of different prednisolone (CAS 50-24-8) tablet formulations (Prednisolon Ferring 2, 5, and 20 mg) was investigated in comparison to a reference formulation. The study was performed in a GCP/ICH-conform manner using a randomized cross-over design in 13 healthy volunteers. With respect to the pharmacokinetic parameters Cmax (maximal prednisolone concentration), AUC0-12 h (area under the concentration-time curve until 12 h after drug intake), AUC0-infinity (area under the concentration-time curve until infinity), and t1/2 (elimination half-life time), 10 x 2 mg prednisolone tablets did not show any relevant differences as compared to the reference (1 x 20 mg) meaning that the 90% confidence intervals were within the given 0.80-1.25 limits for the decision of bioequivalence. Although not statistically significant, tmax (time to reach the maximal prednisolone plasma concentration) was 11 min shorter regarding the test preparation as compared to the reference. The pharmacokinetic parameters of 4 x 5 prednisolone tablets were also well in accordance with the reference. The most important parameters Cmax, AUC and t1/2 were within the defined limits for the acceptance of bioequivalence and, in addition, tmax did not show any significant differences. The 20 mg prednisolone tablet formulation showed almost identical parameters of Cmax, AUC, t1/2 und tmax in comparison to the reference substance. Taken together, the results of the bioavailability parameters indicate the bioequivalence of the three prednisolone test preparations as compared to the reference.     

Bioequivalence of two oral ciprofloxacin tablets formulations

The relative bioavailability of a new 750 mg tablet formulation of ciprofloxacin (test formulation supplied by Dr. August Wolff GmbH and Co., Germany) was compared with that of Ciprobay tablets 750 mg (reference formulation from Bayer Vital GmbH and Co., Germany). Twenty-four healthy volunteers (12 male and 12 female) were included in this single-dose, 2-sequence, crossover randomized study. Blood samples were obtained prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 30 hours after drug administration. Plasma concentrations of ciprofloxacin were determined by HPLC. No differences were found when the in vitro dissolution profiles of both formulations were compared. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were tested for bioequivalence after log-transformation of data, and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following mean values for the test/reference ratios (90% standard confidence intervals in parenthesis (ln-transformed data): 1.01 (0.95-1.07) for AUC(0-t), 0.99 (0.93-1.05) for AUC(0-infinity), 1.05 (0.97-1.14) for Cmax and 1.06 (0.97-1.15) for Cmax/AUC(0-infinity). The nonparametric confidence interval for tmax was 0.77-1.15. All parameters showed bioequivalence between both formulations as their confidence intervals were within the bioequivalence acceptable range of 0.80-1.25 limits; the 90% confidence interval for tmax slightly exceeded limits of bioequivalence. We conclude that both formulations show bioequivalence for both the rate and the extent of absorption.     

Bioequivalence of ciprofloxacin tablet formulations assessed in Indonesian volunteers

AIM: Determination of the bioequivalence of two ciprofloxacin tablet formulations (test formulation manufactured by Novell Pharmaceutical Laboratories, Indonesia, reference formulation from Quimica Farmaceutica Bayer, Spain). SUBJECTS AND METHODS: 24 healthy volunteers received each of the two ciprofloxacin formulations at a dose of 500 mg in a 2-way crossover design. Blood samples were obtained prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and24h after drug administration. Plasma concentrations of ciprofloxacin were monitored using high-performance liquid chromatography over a period of 24 h after administration. The pharmacokinetics parameter AUC0-24h, AUC0-infinity and Cmax were tested for bioequivalence after log-transformation of data and ratios of tmax were evaluated non-parametrically. RESULTS: The point estimates and 90% confidence intervals for AUC0-24h, AUC0-infinity and Cmax were 97.55% (92.71 - 102.6%), 97.63% (92.90 - 102.59%) and 95.84% (89.95 - 102.10%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. CONCLUSION: These results indicate that two medications of ciprofloxacin are bioequivalent and, thus, may be prescribed interchangeably.     

Bioequivalence study of two tablet formulations containing rimonabant 20 mg in healthy Indian subjects

A randomized, two-treatment and two-way crossover study on twelve healthy Indian male subjects was conducted to assess the bioequivalence of two tablet formulations containing 20 mg of rimonabant (CAS 158681-13-1). Both of the formulations were administered orally as a single dose with a 45-day washout period between two dosing sessions. The content of rimonabant in plasma was determined by a validated HPLC method with UV detection. The formulations were compared using the parameters area under the plasma concentration-time curve (AUC(0-t)), area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax). The results of this investigation indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity) and Cmax values of the two preparations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 96.62% of that of the reference formulation. Thus, these findings clearly indicate that the two formulations are bioequivalent in terms of rate and extent of drug absorption.     

Pharmacokinetics of diclofenac after oral administration of its potassium salt in sachet and tablet formulations

This paper reports the results of a pharmacokinetic study involving 24 healthy volunteers and designed to characterise the rate and extent of diclofenac absorption after the administration of a single dose of diclofenac (CAS 15307-86-5) potassium salt 50 mg in sachet (Voltfast) and tablet (Cataflam) formulations. Timed plasma concentrations of diclofenac during a 12-h-period after dosing were measured by means of HPLC with UV detection at 275 nm and a quantification limit of 10 ng/ml; the method was fully validated for pharmacokinetic purposes. These plasma concentrations were used to calculate Cmax, tmax, trapezoidal AUC0-t and AUC0-infinity and t1/2 by means of noncompartmental analysis. Cmax and tmax are the parameters expressing the rate of absorption, whereas the AUCs reflect the extent of absorption. The rate of absorption with the sachets proved to be very fast, reaching peak values at 10 min in seven subjects and at 15 min in the remaining subjects: mean time was 13.68 min, with concentrations at 5 min being 38% of Cmax. The average time to peak concentration with the tablets was 53.10 min. The extent of absorption of the sachets and tablets was similar, with AUC0-infinity values of respectively 1362 and 1214 ng.ml-1.h, and a 90% confidence interval 1.05-1.20. The highly soluble potassium salt of diclofenac was rapidly absorbed, especially in its sachet formulation, and thus appears to be an invaluable analgesic agent that is particularly useful for quick pain relief.     

Bioavailability of a new effervescent tablet of diclofenac

OBJECTIVE: The bioavailability of a newly developed effervescent tablet containing 50 mg diclofenac Na (DIC-effervesc) was investigated and compared with an enteric-coated dragée (DIC-enteric). SUBJECTS AND METHOD: 24 healthy, male and informed volunteers (mean body weight 78.8 kg, mean age 31.9 years) received in a randomized cross-over design a single dose of 50 mg diclofenac as DIC-effervesc and DIC-enteric. A total of 19 blood samples were obtained before and up to 12 h after administration according to the different properties of the galenic formulation. Diclofenac was analyzed by a sensitive HPLC method with a lower limit of quantification of 20 ng/ml. The bioavailability was compared as ratios of the geometric means of AUC0-infinity and Cmax. RESULTS: DIC-effervesc shows no lag time, a tmax within 30 min and a double peak of Cmax in 15/24 subjects. The mean Cmax (arithm. mean +/- SD) for DIC-effervesc is 950+/-341 ng/ml (first Cmax) and for DIC-enteric 1364+/-335 ng/ml. The mean AUC0-infinity, (arithm. mean +/- SD) amounts to 1097+/-210 ng/ml x h for DIC-effervesc and 1262+/-220 ng/ml x h for DIC-enteric. Based on the point estimator and the 90% interval DIC-effervesc is bioequivalent in respect to amount absorbed (86.4%; 81.8 - 91.3%). DIC-effervesc was well tolerated. CONCLUSION: The new effervescent tablet of diclofenac Na shows a rapid absorption without lag time, the same amount of absorption and a slightly lower Cmax (caused by a double peak phenomenon) in comparison to the enteric-coated dragee. A rapid onset of therapeutic effect is postulated in acute pain disorders.     

Pharmacokinetics and gamma scintigraphy evaluation of two enteric coated formulations of didanosine in healthy volunteers

AIMS: The aims of the study were to evaluate the bioavailability of didanosine from the encapsulated enteric coated beads (1 x 200 mg; enteric beads) and enteric coated mini-tablets (4 x 50 mg; enteric tablet) formulations relative to the chewable/dispersible buffered tablets (2 x 100 mg; buffered tablet), and to study their rate of gastrointestinal transit. METHODS: This was a single-dose, randomized, three-way crossover study in 18 healthy male volunteers. A 200 mg dose of didanosine was given in each period and each formulation contained a gamma radiation-emitting isotope. Pharmacokinetic parameters determined were Cmax, tmax, AUC(0, infinity ) and t1/2. Bioequivalence was assessed using the confidence interval (CI) of 0.80, 1.25 for Cmax and AUC(0, infinity ). Scintigraphic images were recorded and gastrointestinal transit profiles were generated. RESULTS: The point estimate and 90% CI of the ratio of Cmax for the enteric beads and enteric tablet relative to the buffered tablet was 0.71 (0.59, 0.85) and 0.55 (0.46, 0.66), respectively. The tmax was significantly different for the enteric beads (median, 1.33 h) and the enteric tablet (median, 2.83 h) than for the buffered tablet (median, 0.67 h). The AUC(0, infinity ) satisfied the bioequivalence criteria, and the point estimate and 90% CI of the ratio were 1.02 (0.91, 1.15) and 0.92 (0.82, 1.04) for the enteric beads and enteric tablet, respectively. The AUC(0, infinity ) values appeared to be less variable with the enteric beads (% CV = 19%) than with the enteric tablet (% CV = 33%). The t1/2 values were not significantly different between formulations, and the mean values ranged from 1.82 to 1.92 h. Inspection of the individual scintigraphy profiles and concentration-time curves suggested that didanosine was absorbed throughout the small intestine. Gastrointestinal transit parameters were higher for both enteric formulations than for the buffered tablet, indicating slower transit of the enteric formulations. Between the enteric formulations, gastric emptying was slower for the enteric beads than for the enteric tablet; however, plasma didanosine concentrations were observed sooner for the enteric beads, suggesting that the enteric coat for the beads dissolved more rapidly. CONCLUSIONS: The enteric beads and enteric tablet formulations of didanosine were equivalent to the buffered tablet in their extent of absorption. Although the gastric emptying of the enteric tablet was faster, based on the rapid uncoating and the lower variability in AUC, the enteric beads were chosen for further clinical development.     

In vitro and in vivo equivalence of two oral atenolol tablet formulations

A randomised, cross-over, open study of bioequivalence between two different atenolol (CAS 29122-68-7) tablet formulations is presented. An in vitro comparative study between the two formulations was also performed. Both products meet the USP 23 (United States Pharmacopea) specification. The values of similarity factor (f2) and difference factor (f1) obtained ensure sameness or equivalence of the two dissolution curves. Twenty-four healthy volunteers (male/female) participated in the bioequivalence study. Each treatment was given as a single 100-mg tablet following an overnight fast. Atenolol concentrations in plasma were determined up to 30 h after treatment by HPLC. The pharmacokinetic parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity were tested for bioequivalence after logarithmic transformation of data and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following test/reference ratios and their 90% confidence intervals (90% CI): 1.06 (0.99-1.13) for AUC, 1.07 (0.97-1.18) for Cmax, and 0.99 (0.94-1.07) for Cmax/AUC0-infinity. The 90% CI for tmax was 0.91-1.23. All parameters showed bioequivalence between both formulations. A discrete fall in both systolic (SBP) and diastolic (DBP) blood pressure was observed after the drug administration. The fall extent (approximately 11 mmHg in supine position) and the time course of both parameters after the drug administration was similar for both formulations. Minimal values for SBP and DBP were achieved at 6 h after the drug administration for both formulations. Heart rates were also reduced after the administration of both formulations of atenolol in a similar extent (12 b.p.m.) and following a similar time profile (i.e. maximal reductions were observed between 1 and 3 h after the drug administration). It can be concluded that both formulations are equivalent in vitro and in vivo.     

In vivo pharmacokinetic-pharmacodynamic relationship and in vitro equivalence of two oral furosemide tablet formulations

A randomized, cross-over, open study of bioequivalence between two different furosemide (CAS 54-31-9) formulations was performed; simultaneously, diuretic effects (urine output, sodium, potassium and chloride excretion) were also compared. Both products meet the British Pharmacopoeia specification and the results of a previous in vitro comparative study ensure equivalence of the two dissolution curves. Twenty-four healthy volunteers (male/female) participated in the bioequivalence study. Each treatment was given as a single 40-mg tablet following an overnight fast. Furosemide concentrations in plasma (measured by HPLC) and electrolyte amounts in urine were determined up to 12 h after treatment. The pharmacokinetic parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity were tested for bioequivalence after ln-transformation of data and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following test/reference ratios and their 90% confidence intervals (90% CI): 1.06 (0.94-1.19) for AUC0-infinity, 1.12 (0.96-1.31) for Cmax, and 1.06 (0.97-1.16) for Cmax/AUC0-infinity. The 90% CI for tmax was 0.55-1.00. Bioequivalence between both formulations was concluded for all parameters except for tmax. No significant diuretic differences between both formulations (test and reference) were observed after drug administration in relation to the baseline period. Systolic and diastolic blood pressure and heart rate showed a similar time-course after the drug administration and there were no differences between both formulations. Both products were well tolerated. It can be concluded that both formulations are equivalent in vitro and in vivo.     

Bioequivalence between omeprazole MUPS 20 mg as tablet and omeprazole MUPS 20 mg as tablet encapsulated in a hard gelatine capsule

AIMS: To investigate pharmacokinetic characteristics of omeprazole MUPS 20 mg tablets and its encapsulated form. MATERIAL AND METHODS: Bioequivalence of omeprazole MUPS 20 mg tablet (Reference) and omeprazole MUPS 20 mg tablet in a hard gelatine capsule (Test) was evaluated in a randomized, 2-period crossover study in 38 healthy male Caucasian subjects who received a single oral dose of 20 mg omeprazole in each study period. Serum concentrations of omeprazole MUPS 20 mg were measured using an HPLC assay. In addition, in vitro dissolution profiles were studied. RESULTS: Both formulations were bioequivalent as assessed by the primary pharmacokinetic characteristics AUC(0-infinity) and Cmax, the corresponding ratios (Test/Reference) being 0.97 and 0.98, respectively. Thus, the 90% CI of these ratios were within the equivalence range of 0.8 to 1.25 for AUC(0-infinity) (CI 0.90-1.04) and 0.67 to 1.50 for Cmax (Cl 0.86-1.10). The ratios of the secondary criteria, Cmax/AUC(0-infinity) and t 1/2, were also within the equivalence range. Median tmax of Reference and Test was identical. Both formulations revealed comparable dissolution profiles with high batch conformity and homogeneity releasing > 80% omeprazole within 1 hour. Both study formulations were well tolerated without relevant differences. CONCLUSION: The encapsulation of omeprazole MUPS 20 mg tablets does not influence the extent and rate of absorption as indicated by the AUC and Cmax ratios. Thus, bioequivalence could be demonstrated.     

Bioavailability of new formulations of amoxicillin in relation to its absorption kinetics

The newly developed amoxicillin (Flemoxin) formulations, a film-coated tablet (A) and an effervescent tablet (B) were tested for bioavailability against a commercial reference formulation (C). The content of amoxicillin in each formulation was 1000 mg. The cross-over study involved 12 healthy volunteers. Blood samples were taken at 10 time intervals after administration and plasma analysed for amoxicillin concentration by bio-assay. Numerically, the effervescent formulation had a superior mean bioavailability over both other formulations, but the difference failed to reach statistical significance due to quite large individual variations. A striking point emerging from a pharmacokinetic treatment of the data was the zero-order nature of the amoxicillin absorption. Re-evaluation of some published data on amoxicillin serum or plasma concentrations, with sufficient data points in the absorption phase, confirmed this observation. This absorption behaviour of amoxicillin is discussed. Assuming the same volume of distribution of amoxicillin for the three formulations, it could be calculated that the mean zero-order rate constant for the effervescent formulation B exceeded that for formulations A and C by a factor of 1.9 and 1.5, respectively. Thus, formulation B shows the most rapid absorption of amoxicillin in accordance with its administration in an already dissolved form.     

Bioequivalence study of finasteride. Determination in human plasma by high-pressure liquid chromatography coupled to tandem mass spectrometry

Two different finasteride (CAS 98319-26-7) tablet formulations were evaluated for their relative bioavailability (Flaxin tablets 5 mg, as the test formulation vs reference formulation, tablets 5 mg) in 23 healthy male volunteers who received a single 5 mg oral dose of each preparation. The study was open, randomized with a two-period crossover design and a 7-day washout period. Plasma samples were obtained over a 48-h interval. The finasteride concentrations were determined by high-pressure liquid chromatography (HPLC) coupled to tandem mass spectrometry (LC-MS-MS). The analytical method developed has a limit of quantitation (LOQ) of 0.50 ng/ml in plasma. For the quality control the measured concentration was 2.05 +/- 0.14 ng/ml (mean +/- SD, n = 30) with a precision of 6.9% and an accuracy of 2.55% at a concentration of the starting solution of 2.00 ng/ml, while with 20.00 ng/ml starting solution the measured concentrations were 20 +/- 0.80 ng/ml (n = 30) with a precision of 3.81% and an accuracy of 0.09%. From the plasma finasteride concentration vs time curves the following pharmacokinetics parameters were obtained: AUC0-48, AUC0-infinity, Cmax, Cmax/AUC0-48, Ke, elimination half-life and tmax. Geometric mean test/reference formulations individual percent ratio was 95.71 for AUC0-48 h and 88.70% for Cmax. The 90% confidence interval for the geometric mean of the individual ratio test/reference formulations was 95.70-120.20% for AUC0-48 h, 94.60-121.30 for AUC0-infinity and 88.70-108% for Cmax. Since for both Cmax or AUC the 90% Cl values are within the interval proposed by the Food and Drug Administration, the test formulation is bioequivalent to the reference formulation for both the rate and extent of absorption after single dose administration.     

A randomized, crossover study to determine bioequivalence of two brands of dexibuprofen 400 mg tablets in healthy Asian adult male subjects of Indian origin

AIM: To estimate the bioavailability and evaluate bioequivalence of a single dose of a dexibuprofen tablet (test formulation, containing dexibuprofen 400 mg, manufactured by Emcure Pharmaceuticals Ltd., Pune, India) and to compare it with that of a single dose of a Seractil tablet (reference formulation, containing dexibuprofen 400 mg, manufactured by Genus Pharmaceuticals, Bershire, UK) under fasting conditions. SUBJECTS AND METHODS: Using a two-treatment, two-period, two-sequence, randomized crossover design, test and reference formulations were administered as individual single doses to 24 healthy adult Asian male subjects of Indian origin under non-fed conditions, with 4 days washout period between dosing. 17 blood samples were drawn from each subject over a 12-hour period. Pharmacokinetic parameters, Cmax, AUC0-t, AUC0-infinity and Cmax/AUC0-infinity were calculated from the plasma concentration-time data of each individual and during each period by applying non-compartmental analysis. Analysis of variance was carried out using logarithmically transformed and non-transformed values of the stated pharmacokinetic parameters. Data for test and reference formulations were analyzed statistically to test for bioequivalence of the two formulations. RESULTS: All 24 subjects who received the two formulations on two occasions with a washout period of 4 days, completed the study and provided an adequate amount of blood at each sampling point. After oral administration the values of Cmax (microg/ml), tmax (h), AUC0-t (microg/ml x h), AUC0-infinity (microg/ml x h) for reference and test formulations were 23.501 and 22.948, 1.156 and 1.281, 69.795 and 68.455, and 72.454 and 70.208, respectively. ANOVA and CI test showed no significant (p > 0.05) variation in these pharmacokinetic parameters of test and reference formulations. When the AUC0-t values for both formulations for non-transformed and log-transformed data were compared, the test formulation showed a bioavailability of 98.08% and 99.56%, respectively, as compared to reference formulation. These values are within the acceptance limit of 80 - 120%. No adverse events were observed in any of the subjects during the two runs of the study. Both clinical and laboratory parameters of all subjects showed no clinically significant changes. CONCLUSION: The test formulation containing dexibuprofen 400 mg (manufactured by Emcure Pharmaceuticals Ltd., Pune, India) was bioequivalent to reference formulation (Seractil, manufactured by Genus Pharmaceuticals, Berkshire, UK). Both formulations were well tolerated. The test formulation can be considered a pharmaceutically and therapeutically equivalent alternative to Seractil.     

Bioavailability of propranolol hydrochloride tablet formulations: application of multiple dose crossover studies

Two multiple dose crossover pharmacokinetic studies were carried out to determine the steady-state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal tablets. In Study I, 24 healthy volunteers were dosed with 4 x 10 mg test tablets, 1 x 40 mg test tablet, 4 x 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 x 80 mg test tablet, 1 x 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8 h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration-time data for test tablets and reference tablets were superimposable in both studies. Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady-state. Mean AUC, Cmax, tmax, and Cmin values were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal tablets. Therefore, the test tablets and Inderal tablets were determined to be bioequivalent.     

Bioequivalence assessment of three different estradiol formulations in postmenopausal women in an open, randomized, single-dose, 3-way cross-over study.

OBJECTIVE: The aim of the study was to assess the bioavailability of estradiol (E2) following oral, single-dose administration of equimolar doses of three HRT preparations in a 3-way cross-over study in postmenopausal women. METHODS: 18 healthy subjects were enrolled. Free E2 and estrone (E1) serum concentrations were determined using commercially available immunoassay kits. Bioequivalence testing was performed between the following oral formulations: (a) 1.5 mg E2 tablets versus 2 mg E2V tablets; and (b) 1.5 mg E2 plus 0.15 mg DSG tablets versus 1.5 mg E2 tablets. RESULTS: For both E2 and E1 the E2 tablet was bioequivalent with both the E2V and the E2/DSG tablet with respect to the rate and extent of absorption (bioavailability). Although the mean tmax values of the three tablet formulations were similar, the variability was too large to prove formal bioequivalence. CONCLUSION: E2 tablets and E2/DSG tablets were bioequivalent and also bioequivalence of E2 tablets with commercially available E2V was found, which ensures a sequential HRT preparation without large variations in estrogen serum concentrations.     

Bioequivalence study of two capsule formulations containing diacerein 50 mg in healthy human subjects

This study presents the results of a two-way, two-period, two-treatment crossover investigation in 12 healthy Indian male subjects to assess the bioequivalence of two oral formulations containing 50 mg of diacerein (CAS 13739-02-1). Both formulations were administered orally as a single dose separated by a one-week washout period. The content of diacerein in plasma was determined by a validated HPLC method with UV detection. The formulations were compared using the parameters area under the plasma concentration-time curve (AUC(0-t)), area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax). The results of this study indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity) and Cmax, values of the two preparations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 96.63% of that of the reference formulation. Thus, these findings clearly indicate that the two formulations are bioequivalent in terms of rate and extent of drug absorption.     

Effervescent and standard formulations of ranitidine—a comparison of their pharmacokinetics and pharmacology

Background : An effervescent formulation of ranitidine may be absorbed faster and achieve a faster onset of action than conventional tablet form. The aim of this study was to compare the effects of effervescent formulations of ranitidine with equivalent dose standard tablets, in terms of intragastric pH and plasma pharmacokinetics in the initial 6 h following dosing.
Methods : Fifteen fasting healthy males, aged 18–31 (mean 29) years, were each randomly given, at weekly intervals, 150 mg standard and effervescent ranitidine and 300 mg standard and effervescent ranitidine. Ambulatory gastric pH was performed and plasma drug levels measured at regular intervals.
Results : Plasma ranitidine levels increased more rapidly with both effervescent formulations compared with standard tablets as indicated by mean area under curve (AUC) at 1 h ( P <0.001). However, the pH profiles produced by all four treatments were similar with a steep rise in pH at 40–60 min to give a sustained level of pH 7 for the following 5 h. The effervescent formulations produced a transient rise in pH immediately following dosing, and for 300 mg this rise was significantly different at 10–20 min compared with the standard tablet (median pH 4.75 vs. 2.3, P <0.05).
Conclusions : Plasma drug levels increase more rapidly following effervescent ranitidine. Effervescent and standard formulations of 150 and 300 mg are all equally effective in producing gastric pH 7 after 1 h. However, effervescent formulations produce an early transient rise in pH which may be of clinical benefit.     

The bioavailability of ofloxacin from several formulations

The bioavailability of ofloxacin after a single dose of one of two tablet formulations (200 or 400 mg) or a liquid formulation (1.67 mg/ml) was investigated in 24 healthy male volunteers in an open randomized, crossover design study with a 5-day wash-out period between doses. Plasma concentrations of ofloxacin were determined at various times after administration by a sensitive and specific High Pressure Liquid Chromatography (HPLC) method. Ofloxacin was well absorbed after each administration, although somewhat more slowly after the tablet formulations than the solution. Mean AUC values of 31.8, 31.3, and 31.3 micrograms.hr/ml were calculated after administration of the solution, 2 x 200 mg tablets and a 400 mg tablet, respectively. Thus, the bioavailability of the tablets was in excess of 98% that of the liquid reference. Mean Cmax values of 4.4, 3.7 and 3.7 micrograms/ml were observed at Tmax values of 0.8, 1.6 and 1.8 hours after administration of the solution, 2 x 200 mg tablets and a 400 mg tablet, respectively. The drug was well tolerated and no adverse effects necessitating subject withdrawal were noted during the study.     

Bioequivalence study of two fluoxetine capsule formulations in healthy Middle Eastern volunteers

OBJECTIVE: To assess the bioequivalence of two fluoxetine hydrochloride capsule (20 mg) formulations (Fluoxicare capsule from Pharmacare Ltd., Chemicals and Cosmetics, Ramallah, Palestine, as test formulation, and Prozac from Eli Lilly Ltd., Basingstoke, UK, as reference formulation). DESIGN AND METHODS: The study was conducted open with a randomized 2-period crossover design and a 6-week washout period. Participants were 24 healthy male volunteers aged 18-28 years, divided into 2 groups of 12 subjects. One group was given the originator drug (reference formulation), and the other was given the test formulation. Blood samples were obtained at baseline and at 14 time points during the interval 0-96 hours after drug administration. The concentrations of the samples were assayed spectrophotometrically at 220 nm using a Shimadzu 160 A UV-visible spectrometer. We calculated the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and time of maximum plasma concentration (tmax) for each subject. Logarithmic transformation of the AUC and Cmax was used for the statistical analyses and to assess the bioavailability of the two formulations, using analyses of variance (ANOVA) and Satherwait t-tests for unequal variances. The ANOVA performed of tmax in Cmax, and in AUC provided the appropriate intra-subject variance estimates to evaluate the 90% confidence intervals for the differences between study variables after administration of the test and reference formulations. Statistical analyses were conducted on AUC 0-4 as the extrapolated part of the AUC, a truncated area approach was adapted. RESULTS: The mean pharmacokinetic parameters for both of the drugs under study were as follows: Cmax = 61.24 (+/- 12.96) ng/ml for the test formulation, and for the reference formulation Cmax = 61.39 (+/- 14.1) ng/ml, the effects were statistically equivalent. The tmax for the test formulation was 8.25 (+/- 1.7) and 7.33 (+/- 0.96) for the reference formulation. The area under the curve to infinity (AUC 0-infinity (ng, day/ml)) for the test formulation and for the reference formulation were 293.02 (+/- 52.69) and 296.15 (+/- 61.69), respectively. CONCLUSIONS: The two formulations had equivalent pharmacokinetic parameters, were well-tolerated, and their relative bioavailability was 98.94%.