Comparison of the antinociception produced by two oral formulations of ibuprofen: ibuprofen effervescent vs ibuprofen tablets

Objective: The aim of this study was to compare the dose-related effects of both ibuprofen tablets and ibuprofen effervescent [placebo, 400 and 800 mg ibuprofen (Aktren)] on phasic pain. Patients: Twenty volunteers participated in this randomized, double-dummy, fivefold crossover study. Methods: Measurements were obtained before and 15, 60 and 240 min after drug administration. Pain was produced by CO₂ pulses applied to the left nostril. Subjects rated the intensity of the painful stimuli by means of a visual analogue scale. In addition, chemosomatosensory event-related potentials were recorded. Results: In line with previous work, ibuprofen produced a dose-related decrease in pain-related potential amplitudes P1N1, indicating its antinociceptive effects. Higher plasma concentrations of ibuprofen were reached 15–40 min after administration of the effervescent while ibuprofen tablets had a t_max 60–90 min after administration. In addition, 60 min after intake of the effervescent a prolongation of the latencies of the potentials was observed, possibly reflecting superior antinociceptive properties when compared to ibuprofen tablets. In addition, the effervescent appeared to have more consistent effects on intensity estimates compared to ibuprofen tablets. Received: 13 June 1996 / Accepted in revised form: 22 November 1996     

Pharmacokinetics and bioequivalence of two ibuprofen formulations

In an open controlled randomized cross-over study in 16 healthy male and female volunteers the bioavailability of ibuprofen (CAS 15687-27-1) sugar-coated tablets (Dolo-Dolgit) was tested versus film-coated tablets containing ibuprofen 600 mg. As it results from the AUC evaluation, the bioavailability of both preparations is very good and almost identical. The ibuprofen concentrations achieved after administration of the test preparation, however, are significantly higher (Cmax = 52.03 micrograms/ml) than those achieved after the reference preparation showing a Cmax of 40.32 micrograms/ml. The tmax of 1.0 h is also significantly shorter than after the reference preparation (tmax = 1.5 h). The t1/2 beta after both the test and the reference preparation is within the known range, i.e. 1.8 h and 1.4 h, respectively. Even in long-term treatment with high dosages, administered 3-4 times daily, there is no accumulation of the active ingredient. Concerning the therapeutic relevance, special attention is to be given to the different time-dependent drug concentrations in the central compartment and in the target compartment. Both the higher Cmax and the shorter tmax achieved following administration of the test preparation are of therapeutic relevance.     

The antipyretic effect of ibuprofen and acetaminophen in children

OBJECTIVE: To determine whether evidence in the medical literature supports ibuprofen or acetaminophen for reducing fever in children. METHODS: Both MEDLINE and the Science Citation Index were searched using various medical subject headings for all articles published worldwide from 1966-2000. The language of publication was not restricted. RESULTS: Initially, 4132 articles were found that dealt with either ibuprofen or acetaminophen. Limiting these articles to humans and children, and cross-referencing with the Science Citation Index resulted in 68 articles; 22 satisfied the inclusion criteria and were further assessed for validity, design, and methods of reporting data. CONCLUSION: Acetaminophen and ibuprofen have equal tolerability. Acetaminophen produced a greater body temperature reduction at 0.5 hour after intervention compared with ibuprofen. However, ibuprofen provides a longer duration of antipyretic effect than acetaminophen 4 hours after intervention, and the initial temperature decrement lasts longer.     

Rapidly absorbed solid oral formulations of ibuprofen using water-soluble gelatin

Rapidly absorbed oral dosage forms of ibuprofen using water-soluble gelatin (hydrolysate of common gelatin: mean mol. wt: 6000) have been studied and compared with tablets prepared with common gelatin (mean mol. wt: 100,000) and commercial tablets. Spray-dried and speed-kneaded powders, two types of granules and tablets were prepared with water-soluble gelatin. The in-vitro dissolution rates of water-soluble gelatin preparations were significantly faster than those of commercial tablets, whereas the tablets prepared using common gelatin had slower dissolution rates than commercial tablets. Water-soluble gelatin enhanced the dissolution rate of ibuprofen by improving the wettability of the drug particle surface by water, without any interaction in solution and the solid state. The absorption behaviour of various preparations was evaluated in four beagle dogs. The peak concentration time (tmax) of the water-soluble gelatin preparations was significantly shorter than that of tablets prepared with common gelatin and commercial tablets. The maximum concentration (cmax) and the area under the serum concentration-time curve (AUCo-10 h) were similar in all cases. The serum concentration profiles of water-soluble gelatin solid preparations were almost the same as those of the solutions. On the other hand, the profiles of the common gelatin tablets were similar to those of the commercial tablets. The mean absorption time (MAT) from water-soluble gelatin preparations was about 0.7 h, while the MAT from commercial tablets and common gelatin tablets was about 1.2 h. The differences in the MAT of water-soluble gelatin preparations and commercial tablets or common gelatin tablets were the same as the differences in mean dissolution time (MDT) in gastrointestinal fluid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gastrointestinal tolerability of ibuprofen administered in two pharmaceutical formulations

Ibuprofen (CAS 15687-27-1) is a nonsteroidal antiinflammatory drug endowed with analgesic, antiinflammatory and antipyretic activity. The main side effect of ibuprofen and nonsteroidal antiinflammatory agents is addressed to disturbances of the gastrointestinal tract, like gastric pyrosis, gastric and intestinal damage. A pharmaceutical formulation of ibuprofen in fast melting tablets consisting in gastroprotected microgranules to be ingested without concomitant water intake (Cibalginadue Fast, hereinafter referred to as test) was compared in this trial with a formulation of ibuprofen in tablets (reference) on 18 healthy volunteers in terms of gastrointestinal and general tolerability. Both the formulations are present on the market. The two formulations were administered according to a two-period, two-formulation, two-sequence, cross-over design in repeated dose regimen to steady state with wash-out. The dose was 400 mg (2 strengths) b.i.d. over 7 days. Before, during and after each study period general tolerability was carefully checked from blood/urine biochemical parameters, adverse events experienced and vital signs. The target parameters were the gastric permeability to sucrose and the intestinal permeability to lactulose and mannitol, which were administered orally and assayed in the urine excreted during a 6-h period. Urinary excretion > 0.15% of sucrose and > 0.04 of the lactulose to mannitol ratio are considered expression of increased gastric and intestinal permeability, respectively. Three volunteers treated with the reference showed an increased gastric permeability > 0.15%. Neither other gastric nor intestinal increased permeability was detected. Occult blood in faeces was negative in all the cases. The incidence of adverse effects experienced was higher with the reference (9 volunteers) than with the test (5 volunteers). In details gastric pyrosis was experienced by six volunteers treated with the reference and only by two volunteers treated with the test. The whole tolerability was better with the test formulation than with the reference, even if these differences did not reach any statistically significant degree. The better tolerability of the test was attributed to its gastroprotection.     

Bioavailability of two dermal formulations of S(+)ibuprofen in rabbit

Ibuprofen (CAS 15687-27-1) is widely used in painful situations and, usually, is administered in the racemic form. Since enantiomers may exert different pharmacodinamic and pharmacokinetic effects, the pharmaceutical industry has placed new emphasis on the preparation of new formulations of enantiomerically pure drugs that must be pharmacokinetically characterised prior to their administration in human beings. In this study, the absorption kinetics of two topical formulations of S(+)ibuprofen in rabbits was investigated. The S(+)ibuprofen levels in rabbit plasma were determined by a non-chiral HPLC method, whereas the absence of the R(-)ibuprofen enantiomer in plasma was confirmed by a chiral HPLC method. The results showed that S(+)ibuprofen was absorbed through the rabbit skin upon administration and the obtained levels varied with the formulation.     

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.     

克拉霉素两种制剂的生物等效性研究

采用微生物管碟检定法，以短小芽孢杆菌ＣＭＣＣ（Ｂ）６３２０２为检定菌，测定了１２名男性健康受试者口服克拉霉素（ＣＲＭ）胶囊（被试制剂）和片剂（标准对照制剂）后不同时刻血浆中活性药物的浓度，绘制了血药浓度－时间曲线。受试者交叉口服含ＣＲＭ５００ｍｇ的被试制剂和标准对照制剂后，血浆药物浓度达峰时间分别为１．３９±０．７４和１．１６±０．４１ｈ，血浆药物浓度峰值分别为２．５４±０．６２和２．７１±０．６１μｇ／ｍｌ，消除半衰期分别为４．５９±０．９９和４．７２±０．８５ｈ，用梯形法计算，ＡＵＣ０→∞分别为２１．７０±２．７１和２２．４２±３．５３ｈμｇ／ｍｌ。被试制剂中ＣＲＭ的相对生物利用度平均为（９９．３±１０．３）％，经统计学分析与对照制剂生物等效。两种制剂中ＣＲＭ的药动学过程均符合一室开放模型     

Comparative bioavailability of two oral formulations of ranitidine

The current requirement of the Mexican Authorities to demonstrate the interchangeability of ranitidine formulations is to establish that the dissolution profile of the drug shows similarity. In order to establish if this requirement is adequate, the bioavailability of two formulations that did not meet this similarity were compared. Twenty-five female volunteers received 150 mg ranitidine (Azantac or Midaven) under fasting conditions in two separate sessions using a cross-over design. Plasma samples were obtained at selected times for a period of 12 h and stored frozen at -80 degrees C until analysed. Ranitidine plasma levels were determined and pharmacokinetic parameters were obtained. Values (mean+/-SEM) were: Cmax 528.85+/-25.34 and 563.03+/-33.25 ng/ml, tmax 2.76+/-0.19 and 2.79+/-0.18 h, and AUC12 h 2694.94+/-99.50 and 2648.51+/-133.38 ng.h/ml, for Azantac or Midaven, respectively. No statistically significant difference was obtained in the parameters evaluated. Moreover, 90% confidence limits were 96.6%-116.2% and 90.7%-105.1% for Cmax and AUC12 h ratios, respectively, indicating that the formulations tested are bioequivalent, despite the dissimilarity in the dissolution profile of the formulations. These results suggest that the comparative dissolution profile is not an adequate test to demonstrate the interchangeability of ranitidine formulations.     

Cyclosporine bioavailability of two physically different oral formulations

To assess the comparative bioavailability of two cyclosporine capsule products with different pharmaceutical formulation an open randomized two-period cross over study was conducted in 24 healthy volunteers. Our results, obtained from cyclosporine HPLC determination onto the whole blood samples collected, show that the test cyclosporine non-SMEDDS formulation was not bioequivalent cyclosporine SMEDDS formulation due to a statistically significantly lower absorption rate. The outcome does not support free and full interchangeability in chronic stable graft recipients of the two products studied, unless validated clinical and laboratory conversion protocols for each kind of organ transplantation are enforce.     

Comparative bioavailability between two Tramadol once-daily oral formulations

The aim of this study was to compare the pharmacokinetic profile and oral bioavailability of Tramadol Contramid once-daily (o.d.) 200 mg tablets (Labopharm, Canada) with that of Zytram 200 mg tablets (Zambon, Spain), following single-dose administration in 26 healthy volunteers. The study had an open, randomized, crossover design with a 7-day wash-out. Data from 24 subjects were used for the pharmacokinetic (PK) analysis. Racemic tramadol and racemic O-demethyltramadol (M1) were assayed in plasma using a liquid chromatography/tandem mass spectrometry method. Primary PK parameters estimated were AUC(0-t), AUC(0-infinity), C(max), C(24 h), and T(max). Results were compared using an ANOVA, and the residual variability thereby obtained was used to construct the classical 90% confidence intervals. The parametric Schuirmann's test was also performed. T(max) was analyzed by a nonparametric approach. For both racemic tramadol and racemic O-demethyltramadol, the ANOVA showed a statistically significant formulation effect. Significantly higher values were obtained for Tramadol Contramid o.d. for all PK parameters, except for T(1/2). For Tramadol Contramid o.d., mean tramadol plasma levels were maintained at a plateau level above 200 ng/ml from 4 to 16 h after dose, while for the reference formulation, that level was sustained from 4 to only 6 h. Consistent results for both formulations were obtained for the metabolite. At the end of the dosing interval, plasma tramadol and O-demethyltramadol concentrations were 39% and 49% higher, respectively, for Tramadol Contramid o.d. than those for Zytram (p < 0.0001). Tramadol Contramid o.d. could be considered suprabioavailable to Zytram o.d.     

Evaluation of the absorption from three ibuprofen formulations

The pharmacokinetic differences between two sustained-release 300 mg (A) and 400 mg (B) formulations and a rapid-release 400 mg ibuprofen conventional sugar-coated formulation (C) were compared after a single dose. Mean peak levels of 25.1 micrograms/ml for preparation A (2 X 300 mg), 31.3 micrograms/ml for preparation B (2 X 400 mg) and 68.5 micrograms/ml for preparation C (2 X 400 mg) were reached at 5.3, 3 and 2 hours respectively, after ingestion of the drugs. The individual plasma-level time-profiles for the majority of doses suggested prolonged absorption of product A and B. The absorption from formulations A and B was significantly slower (p less than 0.001 and p less than 0.05 respectively) than that from the conventional tablets. The bioavailability of ibuprofen from sustained-release capsules, was not found to differ significantly from that of ibuprofen from conventional tablets. The relative bioavailability was very close to 100% in almost all subjects (coefficient of variation 14% and 17%). Projections of plasma concentrations upon multiple dosing were made from single dose data. The dosage interval concentration ratio which reflects both the frequency and the entry of the drug into and from the body was much lower for sustained-release formulations (A: 3.0; B: 3.7; C: 12.9).     

Bioavailability investigation of two different oral formulations of doxepin

Two different oral doxepin (CAS 1668-195) formulations (Doxepin-ratiopharm 25 mg film-coated tablets as test preparation and 25 mg dragées of the reference preparation) were investigated in 30 healthy male and female volunteers in order to prove bioequivalence between these preparations. A single 75 mg oral dose (3 units of test or reference preparation) was given according to a randomised two-way cross-over design in the fasted state. Blood samples for determination of plasma concentration of doxepin and its metabolite N-desmethyldoxepin were collected at pre-defined time points up to 168 h following drug administration. A wash-out period of three weeks separated both treatment periods. Doxepin and N-desmethyldoxepin plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 193,463 pgh/ml (test preparation) and 197,988 pg h/ml (reference preparation) for doxepin as well as values of 313,298 pg h/ml (test preparation) and 306,663 pgh/ml (reference preparation) for N-desmethyldoxepin for the parameter AUC0-infinity demonstrate a nearly identical extent of drug absorption. Maximum concentrations (Cmax) for doxepin/N-desmethyldoxepin of 15,960.06/6,883.69 pg/ml and 18,614.73/6,846.62 pg/ml were achieved for test and reference preparation. Time to reach doxepin maximum plasma concentration (tmax) was 1.98 h for both preparations and for N-desmethyldoxepin tmax was 4.52 h (test preparation) and 4.15 h (reference preparation). Cmax and AUC0-infinity values were tested for statistically significant differences by means of the Two One-Sided T-Tests procedure following ln-transformation of data. Bioequivalence was assumed if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for ln-transformed AUC0-infinity and 70%-143% for ln-transformed Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.     

Bioavailability investigation of two different oral formulations of methylprednisolone

Two different oral methylprednisolone (CAS 83-43-2) formulations (Methylprednisolon-ratiopharm 8 mg tables as test preparation (T) and tablets of a reference preparation (R)) were investigated in 16 healthy volunteers in order to prove bioequivalence between these preparations. A single 8 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of methylprednisolone plasma concentrations were collected at pre-defined time points up to 16 h following drug administration. A washout period of 3 days separated both treatment periods. Methylprednisolone plasma concentrations were determined by means of a validated HPLC method. Values of 342.53 ng.h/ml (test preparation) and 336.61 ng.h/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 66.58 ng/ml and 70.51 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 2.2 h for both preparations. Cmax and AUC0-infinity-values were tested parametrically by the two one-sided t-test procedure. Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80-125% for AUC0-infinity and 70-143% for Cmax. Based on the results obtained in this study, bioequivalence between Methylprednisolone ratiopharm and the reference preparation was demonstrated.     

Bioavailability investigation of two different oral formulations of Tetrazepam

Two different oral tetrazepam (CAS 10379-14-3) formulations (Tetrazepam-ratiopharm film-coated tablets as test preparation and tablets of a reference preparation marketed in France) were investigated in 20 healthy volunteers in order to prove bioequivalence between these preparations. A single 50 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of tetrazepam plasma concentrations were collected at pre-defined time points up to 96 h following drug administration. A washout period of 14 days separated both treatment periods. Tetrazepam plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 3873.08 ngh/ml (test preparation) and 3930.69 ngh/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 482.08 ng/ml and 465.14 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 1.39 hours for both preparations. Cmax and AUC0-infinity-values were tested parametrically by an analysis of variance (ANOVA). Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for AUC0-infinity and 70%-143% for Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.     

Spectrofluorometric determination of ibuprofen in pharmaceutical formulations

The spectrofluorometric determination of ibuprofen in pharmaceutical tablets, creams and syrup is described. It involves excitation at 263 nm and emission at 288 nm. the linear range is 2-73 mg L(-1). Other drugs or excipients present in the different formulations do not interfere, except in the case of chlorzoxazone containing tablets. Due to its strong absorbance in the spectral range the chlorzoxazone does interfere, so that in this case the proposed method can't be applied.     

布洛芬片剂处方组成的优选

采用均匀设计优选出布洛芬片剂最佳处方组成。按该处方组成压制成的片剂Ａ与市售片剂Ｂ、Ｃ进行体外溶出速率试验。结果表明：外溶出度参数间均匀有显著性差异（Ｐ＜０．０５），说明该方片比市售片释放快 。     

Pharmacokinetic-Pharmacodynamic Modelling of Zopiclone Effects on Human Central Nervous System

Abstract: The present data shows the pharmacokinetics and concentration-effect relationship of a single 7.5 mg oral dose of zopiclone in ten healthy volunteers. Plasma concentrations and effects of zopiclone on central nervous system as quantified by changes in saccadic peak velocity and digit symbol substitution test were measured for 17 hr after ingestion of zopiclone. Pharmacokinetics was described with a linear one-compartment open model. Maximum effects preceded peak plasma zopiclone concentrations causing a clockwise hysteresis, i.e. proteresis, in concentration versus effect loops. Therefore, pharmacodynamics was described both with a tolerance model and a model with distributional pseudo-tolerance where the concentration in the blood sampling site is assumed to equilibrate slower with arterial blood than the site of action of zopiclone. Both models related the changes in pharmacodynamics linearly to changes in zopiclone concentrations. The median (range) values for clearance, volume of distribution and elimination half-life were 21 (15-53) L/hr, 132 (58-161) L and 3.4 (1.7-5.7) hr, respectively. Both pharmacodynamic models were able to describe the relationship between zopiclone concentrations and changes in psychomotor performance equally well. However, because the pharmacodynamics of zopiclone were studied in a non-steady-state situation, the mechanism for proteresis, i.e. true tolerance versus distributional pseudotolerance cannot be identified.     

Bioavailability of two oral formulations of triazolam using radioreceptor assay

The radioreceptor assay (RRA) was used to quantitate plasma triazolam concentrations in eight female volunteers following single 0.5 mg doses of two tablet formulations in a cross-over study. Bioavailability in terms of area under the plasma concentration versus time curve (AUC0 infinity), maximum plasma concentration (Cmax), time to maximum (tmax), and mean residence time (MRT) was not statistically significantly different from one formulation to the other.     

Relative bioavailability of two oral formulations of navelbine in cancer patients

A study was carried out in 14 cancer patients to assess the relative bioavailability of two oral formulations of navelbine. A single 130 mg oral dose of the drug was given according to a randomized two-way crossover design as two capsules: one contained the drug in powder (formulation A, reference); another contained the drug in solution (formulation B). A 7 d washout period separated each dose. Navelbine was rapidly absorbed after administration of either formulation and exhibited a biphasic concentration decay pattern. The peak plasma level was reached within 2 h of administration in most patients. Formulation B resulted in better naveibine absorption with respect to peak plasma concentration (C_max) and area under the plasma concentration—time curves (AUC) than did formulation A as ascertained by analysis of variance (ANOVA). The relative bioavailabilities (solution versus powder) were, respectively, 286.0% and 268.0% as estimated from experimental (0–72 h) and extrapolated (0–∞) AUC.