Pharmacokinetics and absolute bioavailability of ibuprofen after oral administration of ibuprofen lysine in man

The lysine salt of d,l-2-(4-isobutylphenyl)-propionic acid (ibuprofen lysine) was administered as a single oral dose of 500 mg by means of commercially available coated tablets (Imbun).* To assess the absolute bioavailability of ibuprofen after its oral application as a lysine salt, intravenous injections of ibuprofen solutions containing 200 mg and 400 mg of the drug served as reference application. In a partially randomized cross-over design, 8 healthy male volunteers received three different single dose administrations which were separated by wash-out periods of 4 days each. Ibuprofen plasma concentrations were determined by HPLC using direct injection, pre-column enrichment and column switching techniques. From the results of intravenous injections one can deduce linear ibuprofen pharmacokinetics within the considered dosage range, with corresponding AUC0-infinity values of 3786 micrograms * min ml-1 and 7260 micrograms * min ml-1 for the 200 mg and 400 mg doses, respectively. The values of plasma clearances as well as those of different volumes of distribution showed remarkable constancy after evaluation from both intravenous injections. The absorption of orally administered ibuprofen lysine proved to be rapid, resulting in a mean peak plasma level (Cmax) of 31 micrograms ml-1 ibuprofen and in a mean time to peak (tmax) of 45 min. The absolute bioavailability of ibuprofen amounts to 102.7 per cent, indicating a complete absorption of ibuprofen when administered as its lysine salt. Drug tolerability was excellent for the oral administration of ibuprofen lysine as well as for the intravenous treatments with ibuprofen free acid. Only mild and transient adverse drug reactions such as mild burning or dragging sensation during injection or mild redness at the site of injection were reported.     

An evaluation of different ibuprofen preparations in the control of postoperative pain after third molar surgery.

1. Two separate placebo-controlled studies of parallel design were carried out to evaluate the efficacy of single doses (400 mg) of soluble ibuprofen, ibuprofen liquid in a gelatin capsule and ibuprofen tablets (Nurofen), in patients with postoperative pain after third molar surgery. 2. All ibuprofen preparations provided significant pain relief (P less than 0.05) over a 6 h investigation period. 3. Mean pain scores after ibuprofen tablets and ibuprofen liquid in a gelatin capsule were similar. 4. Soluble ibuprofen 400 mg provided an earlier onset of pain relief (20 min) than ibuprofen tablets (30 min). 5. No unwanted effects were reported in the various ibuprofen treatment groups. 6. The ibuprofen preparations evaluated in this study are effective up to 4 h for controlling postoperative pain after third molar surgery. The soluble form is more efficacious with regard to onset of action.     

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).     

Comparative bioavailability of diclofenac hydroxyethylpyrrolidine vs diclofenac sodium in man

Summary A pharmacokinetic study in man has been made of a new dosage form of diclofenac hydroxyethylpyrrolidine (DIEP); soluble salt packed in sachets was compared with diclofenac sodium as enteric coated tablets.Oral DIEP 2×50 mg showed a significant difference in absorption kinetics (ka, lag time and t_max) as compared to oral diclofenac sodium 2×50 mg. A relevant plasma concentration of diclofenac was detected just 15 min after DIEP, while diclofenac sodium produced a measurable plasma concentration only 0.5–1 h after the treatment. C_max and t_1/2 after DIEP and diclofenac sodium were comparable. Comparison of the two AUC values showed that DIEP was bioequivalent to diclofenac sodium (Q=100%).     

Comparison of the bioavailability of dexibuprofen administered alone or as part of racemic ibuprofen

Two bioavailability studies of S(+)-ibuprofen (dexibuprofen) were conducted in healthy volunteers to define the relationship between the bioavailability of the drug after administration of dexibuprofen alone or as part of ibuprofen racemate. Enantioselective plasma drug analysis was used throughout. In the first study, the bioavailability of dexibuprofen from a 400 mg tablet formulation was compared with that from 400 mg in aqueous solution.The tablet formulation did not influence the bioavailability of the drug and dexibuprofen was well absorbed from the gastro-intestinal tract.The second study was divided into three identical parts. Bioavailability of dexibuprofen 200, 400 and 600 mg was compared with its bioavailability from ibuprofen racemate 400, 800 and 1200 mg.The second study showed that the mean relative bioavailability of dexibuprofen to ibuprofen racemate was 0.66, thus enabling the estimation of clinically useful dexibuprofen doses from the usual doses of the racemate. The 95% confidence interval limits did not include 0.5, leading to the conclusion that administering half of the racemate dose would not provide patients with an adequate amount of therapeutically active drug.     

Ibuprofen arginate provides effective relief from postoperative dental pain with a more rapid onset of action than ibuprofen

Ibuprofen is a safe and effective analgesic, but some formulations have a slow onset of action. Ibuprofen arginate is a rapidly absorbed salt designed to promote more rapid onset of analgesia. A clinical trial was conducted in 226 patients with postoperative dental pain to assess the analgesic efficacy and speed of onset of the arginine salt of ibuprofen compared with one of the commercially available forms of ibuprofen. Patients were administered a single dose of either ibuprofen arginate (200 mg or 400 mg), ibuprofen (200 mg or 400 mg), or placebo in this double-blind, randomized trial. To determine the onset of action of the study medication patients were required to note time to "any" pain relief and then time to "meaningful" pain relief, using the two-stopwatch method. Pain intensity and relief were assessed using traditional categorical scales over a 6-h period. Meaningful pain relief was achieved in 42 min and 24 min for ibuprofen arginate 200 mg and 400 mg, respectively, compared with 50 min and 48 min for ibuprofen 200 mg and 400 mg, respectively ( P<0.05). The results for the measurements of analgesic effectiveness [sum of pain intensity difference, total pain relief (TOTPAR), peak pain relief and overall evaluation of treatment] all showed that both doses of ibuprofen arginate and both doses of ibuprofen were significantly better than placebo and both 200-mg and 400-mg ibuprofen arginate doses were significantly better than ibuprofen 200 mg for peak pain relief. Mean plasma ibuprofen concentrations at 30 min and 60 min, respectively, were: ibuprofen arginine 200 mg, 13.9 micro g/ml and 15.7 micro g/ml; ibuprofen arginine 400 mg, 29.5 micro g/ml and 29.3 micro g/ml; ibuprofen 200 mg 2.5 micro g/ml and 5 micro g/ml; ibuprofen 400 mg, 2.3 micro g/ml and 7.4 micro g/ml. ( P<0.05). Adverse event profiles were similar across treatment groups. These results overall suggest that ibuprofen arginate when taken at doses equivalent to commercially available ibuprofen formulations produces analgesia that is faster in onset.     

Comparison of two different preparations of ibuprofen with regard to the time course of their analgesic effect. A randomised, placebo-controlled, double-blind cross-over study using laser somatosensory evoked potentials obtained from UW-irritated skin in healthy volunteers

In the treatment of painful conditions the time to onset of a drug's analgesic effect is of great relevance. Plain ibuprofen acid (Ibu, CAS 15687-27-1) is relatively slowly absorbed after oral administration (t(max) is about 90-120 min). If, however, ibuprofen is given in form of a lysine salt, absorption is much quicker. It has been shown in pharmacokinetic studies that the maximum plasma concentration after administration of an ibuprofen lysine tablet (IbuLys) is reached at about 35 min after oral administration. The aim of this study was to evaluate the onset and extent of the analgesic effect of 400 mg ibuprofen administered as marketed ibuprofen lysine tablets (two tablets of Dolormin as a single dose) in comparison with standard Ibu tablets (two tablets as a single dose) and placebo (Plc) utilising the objective, quantitative (high resolution) method of Laser algesimetry. The N1-P2 peak-to-peak amplitude of the Laser-induced somatosensory evoked potentials (LSEPs)--measured during the first two hours after administration of study drugs--was the main efficacy parameter for the onset of the analgesic effects. The values obtained during 5 h after administration of the study drugs were used to measure the extent of the analgesic effects. As a main result with respect to the onset of analgesic action, the reduction of the N1-P2 peak-to-peak amplitude was significantly and relevantly more pronounced during the first 2 h after administration of IbuLys than after Ibu (IbuLys vs. Plc: p < or = 0.0020, IbuLys vs. Ibu: p < or = 0.0366). During the same time the amplitudes of the single N1-components of the LSEPs were also significantly smaller after IbuLys than after Plc (p < or = 0.0031) whereas the difference between plain Ibu and Plc was not significant (p < or = 0.1027). As a measure of the extent of analgesic action, the N1-P2 peak-to-peak amplitudes recorded during 5 h after medication were more effectively reduced by IbuLys than by Ibu (IbuLys vs. Plc: p < or = 0.0001, IbuLys vs. Ibu: p < or = 0.0041, Ibu vs. Plc: p (0.383). The reduction of the amplitudes of the single N1-components by IbuLys was significant in comparison to Plc (p < or = 0.0031), but not in comparison to Ibu. During the time of 5 h after medication the attenuating (analgesic) effect of IbuLys on the amplitude of the P2 component of the LSEPs was stronger than that of Plc (p < or = 0.0053) and stronger than that of Ibu (p < or = 0.0058). In summary IbuLys was significantly superior to Ibu with respect to the onset and extent of the analgesic effect. drugs were used to measure the extent of the analgesic effects. superior to Ibu with respect to the onset and extent of the analgesic effect.     

A controlled comparative study of ibuprofen arginate versus conventional ibuprofen in the treatment of postoperative dental pain

The analgesic efficacy of an arginine salt of ibuprofen was compared to one of the commercially available forms of conventional ibuprofen in a 500-patient clinical trial in postoperative dental pain. Patients were administered a single dose of ibuprofen arginate (200 mg or 400 mg), conventional ibuprofen (200 mg or 400 mg), orplacebo in this double-blind, randomized, parallel-group trial. Results demonstrated that ibuprofen arginate was a safe and effective analgesia that was superior to conventional ibuprofen in both the amount of pain relief achieved and the time to onset of pain relief. Onset of analgesia, assessed as the median amount of time to achieve meaningful pain relief, was reached after 32 and 31 minutes with ibuprofen arginate 200 and 400 mg, respectively, and 64 and 58 minutes with conventional ibuprofen 200 and 400 mg, respectively (p < 0.05). Patients treated with ibuprofen arginate rated its overall effectiveness higher than those patients treated with conventional ibuprofen. Adverse event profiles were similar across all treatment groups.     

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.     

Common cold and influenza symptom management: the use of pharmacokinetic considerations to predict the efficacy of a twice-daily treatment for colds and flu

OBJECTIVE: The objective of the two pharmacokinetic studies reported here was to compare the relative bioavailability of an ibuprofen/pseudoephedrine modified-release capsule with each of the active ingredients given alone as standard formulations. STUDY DESIGN: Evaluation of two open, randomised, cross-over studies, one single dose and one multiple dose, in healthy male volunteers. METHODS: Healthy volunteers were randomised in a cross-over design to single or multiple doses of a combination of ibuprofen (600 mg) plus pseudoephedrine (90 mg) in a slow-release formulation and the individual active products alone as standard formulations; ibuprofen 400 mg, pseudoephedrine 60 mg. RESULTS: The single-dose study demonstrated that the bioavailabilities of ibuprofen and pseudoephedrine achieved with the slow-release formulation were not significantly different from those with standard tablets of each ingredient alone. In addition, mean plasma levels of ibuprofen predictive of clinical efficacy were achieved within 0.5-1 h and lasted for 10-12 h thereafter. The time required to reach clinically effective blood levels of pseudoephedrine was longer, starting at approximately 2 h. However, the plasma levels predicted that the clinical effect would then last for at least a further 12 h. Trough levels from the multiple-dose study showed that clinically relevant analgesic and decongestant plasma levels were maintained for 24 h during twice-daily dosing. The slow-release formulation was well tolerated with only mild adverse events. CONCLUSIONS: Blood levels would predict that the present slow-release formulation of ibuprofen plus pseudoephedrine should offer reliable day and night control of cold and flu and sinus symptoms and be associated with a favourable safety profile.     

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.     

Elevation of gastric pH with ranitidine does not affect the release characteristics of sustained release ibuprofen tablets

The effect of elevating gastric pH on the release characteristics of a single unit sustained release (SR) ibuprofen tablet (MOTRIN-SR, Upjohn) was evaluated in 12 young, healthy men. Using a randomized crossover-type design, each subject received three treatments--ibuprofen SR 800 mg, ranitidine 300 mg followed by ibuprofen SR 800 mg, and conventional ibuprofen tablets (2 x 400 mg). Gastric pH, which was monitored radiotelemetrically, was maintained above pH 6 for at least 4 h after pretreatment with ranitidine. In absence of ranitidine, the pH remained mostly below pH 3. Serum levels of ibuprofen were measured for 24 h and urine was collected for 48 h after each treatment. Similarity of the serum levels after the two treatments with ibuprofen SR 800 mg indicated that the release of ibuprofen was unaffected by elevation in gastric pH. Comparison of profiles with the immediate release dosage form indicated that dose dumping did not occur in any subject.     

Single dose bioavailability of two different digoxin tablets

In a single dose bioequivalence study in 10 healthy young adults the absorption profiles and bioavailability of two digoxin containing tablets (A = digoxin-Pharbita 0.25 mg and reference drug B) were compared and related to the in vitro dissolution rate of both tablets. Two tablets of each product (= 0.50 mg of digoxin) were taken at random on an empty stomach; two weeks elapsed between the two treatments. Frequent blood sampling was performed up to 24 h after intake of the dose. Digoxin plasma concentrations were measured by means of radioimmunoassay. No significant differences (p greater than 0.05) were found in the mean values of the peak plasma concentration (cmax), time to peak (tmax) and area under the plasma concentration versus time curve for the period of 0-10 h after drug intake (AUC0-10), although in most subjects the absorption process after intake of product A was slightly faster, with slightly higher peak. This might be related to a slightly faster release of digoxin from the product A dosage form, as was seen from the dissolution test data. The relative bioavailability of product A as compared to product B, accounted for 97.7 +/- 28.7% (mean +/- S.D.). These results indicate, that both products can be considered as being bioequivalent.     

Pharmacokinetics and bioavailability of indoprofen in man

Summary In a pharmacokinetic study of the new analgesic and anti-inflammatory drug indoprofen, plasma levels and urinary excretion were determined in four healthy volunteers after 100 mg and 200 mg iv, and after 100 mg (capsules) and 200 mg (tablets) oral doses. After iv administration, the mean biological half-life (t1/2 ) was about 2 h (range 1.4 to 3.2 h). The apparent volume of distribution Vd ranged between 11 to 17 % of body weight, indicating its limited extravascular distribution. Most of the drug was excreted in urine as glucuronide and a smaller proportion as unchanged indoprofen: the 24 h urinary excretion of these compounds accounted for 67 to 95 % of an iv dose. Peak plasma levels occurred between 30 and 120 minutes after oral administration of 100 mg as capsules or 200 mg as tablets. The mean biological half-life was about 2 h, as after iv administration. The bioavailability of oral doses was assessed using both plasma levels and urinary excretion data. The absorption of capsules and tablets was practically complete, that of the former being faster.     

The comparability of dosage regimens of Lanoxin tablets and Lanoxicaps.

1 Twice daily administration of 0.25 mg digoxin tablets (Lanoxin) or of 0.2 mg digoxin in solution in soft gelatin capsules (Lanoxicaps) produced similar mean steady state plasma digoxin concentrations in ten healthy volunteers. Respective values were 1.07 +/- 0.075 and 0.95 +/- 0.048 ng ml-1. 2 During continued administration, peak plasma concentrations occurred earlier after capsules with a tendency to higher peak levels. However, area under curve determinations over 7 h were similar. 3 Approximately 10% less digoxin was recovered in urine collected in a 12 h dosage interval during the lower dosage administration of capsules. Mean percentage urinary recovery of administered dose was 57% for tablets and 65% for capsules. 4 The enhanced bioavailability of Lanoxicaps was associated with reduced between-subject variability in plasma concentration. 5 Lanoxicaps (0.2 mg) should be approximately equivalent in effect to digoxin tablets (0.25 mg) currently available in the United Kingdom, though improved consistency would be anticipated.     

Effect of food on absorption of indoprofen administered orally to man in two dosage forms.

The influence of food on the bioavailability of two oral dosage forms (100-mg capsules and 200-mg tablets) of indoprofen, a new propionic acid derivative with marked anti-inflammatory and analgesic properties, has been investigated. Plasma levels and urinary excretion of indoprofen were determined both in the fasting state and after a standard meal in healthy volunteers after administration of two 100-mg capsules (4 subjects) and of one 200-mg tablet (6 subjects). Indoprofen in biological fluids was determined by gas-liquid chromatography. The extent of absorption from tablets was not affected by food as indicated from the values of the total area under plasma level curves and urinary excretion of the drug. The rate of absorption was faster after meal than in the fasting state. The opposite was found for capsules, which showed a slightly delayed absorption after food. The results suggest that food may differently influence the absorption pattern of different pharmaceutical forms of the same drug.     

布洛芬新型制剂的研究与开发

综述国内外近年来报道的布洛芬新型制剂的研究与开发，介绍若干具代表性的布洛芬新剂型，包括新型片剂、多层微胶囊、透皮制剂、口腔黏附膜、眼用纳米混悬控释制剂、注射用脂质体凝胶控释制剂及生物可降解聚（乳酸-羟基乙酸）共聚物微球等，这些新剂型普遍提高了药物生物利用度和用药安全性。     

A double-blind, placebo controlled, cross-over comparison of the analgesic effect of ibuprofen 400 mg and 800 mg on laser-induced pain.

1. The analgesic efficacy of single oral doses (400 mg, 800 mg) of ibuprofen on argon laser-induced pain was studied in a double-blind, placebo controlled, three way cross-over comparison. Ten healthy volunteers participated. 2. Pain thresholds and plasma concentrations of the S- and R-enantiomers of ibuprofen were measured every hour up to 8 h after medication. 3. Ibuprofen (400 mg) produced an analgesic effect significantly superior (P less than 0.05) to placebo 1-4 h after medication. Ibuprofen (800 mg) was significantly superior to placebo 2-4 h after administration. No differences were found between 400 mg and 800 mg, when hourly threshold differences were compared. 4. Comparing total analgesic effect (area under effect curve), both active medications were superior to placebo (P less than 0.01-0.05), and 400 mg was superior to 800 mg (P less than 0.05). 5. Peak plasma concentrations of S- and R-ibuprofen occurred between 1.2 and 1.5 h. Concentrations after the 800 mg dose were higher than those after the 400 mg dose at all times.     

Comparative bioavailability and steady state fluctuations of Tegretol commercial and carbamazepine OROS tablets in adult and pediatric epileptic patients.

The comparative bioavailability and steady state fluctuations resulting from the administration of Tegretol 200 mg commercial tablets and carbamazepine OROS controlled delivery tablets were investigated in 22 adult and 12 pediatric epileptic patients. Tegretol commercial tablets were dosed according to previously established clinical regimens of 400 to 2000 mg daily doses divided into four equal or unequal intervals. Carbamazepine OROS was dosed every 12 h at the same corresponding daily dose. Comparisons of the pharmacokinetic parameters AUC, Cmax, Cmin, and tmax at steady state for the two dosage forms demonstrated definitively the bioequivalence of carbamazepine OROS with Tegretol commercial tablet over a 24-h treatment interval.     

Suprofen kinetics in healthy male volunteers after intramuscular injection of increasing dosages

Kinetics of alpha-methyl-4-(2-thienyl-carbonyl)-phenylacetic acid (suprofen, Suprol) a non-narcotic antiphlogistic analgesic, were studied in two clinical experiments. In a bioavailability study (study A) suprofen, given as intramuscular injection was absorbed more rapidly (mean peak plasma time 20.0 min) than from the capsule formulation (mean peak plasma time 57.5 min). With respect to the amount systemically absorbed, measured as area under the plasma concentration-time curve, both dosage forms were equivalent. Individual plasma concentration profiles (study B) were described by a 2-compartmental model with a mean first order absorption rate of 0.095 min-1, a rapid mean disposition rate alpha of 0.025 min-1 and an apparent terminal plasma elimination rate beta of 0.004 min-1. There was dose-independent kinetics and a linear correlation between peak plasma concentration versus dose and area under the curve (AUC) versus dose after intramuscular injection of suprofen up to 200 mg, leading to dose proportional bioavailability data.