In vitro-in vivo correlation exemplified by sustained release formulations of suprofen.

To evaluate some prototype oral sustained release formulations of the analgesic drug suprofen (alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid, Suprol) in vitro-in vivo correlations were performed. Numerical deconvolution led to hypothetical in vivo absorption curves which were in close agreement with the in vitro dissolution profiles. Furthermore, a linear correlation was obtained between the in vivo and in vitro mean residence times calculated from the blood level data.

Suprofen sustained release kinetics in healthy male volunteers. 1st communication: a single dose open crossover bioavailability study of suprofen sustained release tablets versus capsules.

An open crossover study was performed in 12 healthy male volunteers to compare the bioavailability of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) 600 mg sustained release tablets versus the suprofen capsule (2 X 200 mg). The pharmacokinetic profiles in plasma and urine were determined by a HPLC assay. In the dose range studied, the two suprofen formulations were not associated with any clinically significant effects on the blood pressure, heart rate or ECG. The results of the physical and neurological examinations showed no abnormal results. The results of haematology, clinical chemistry and urinalysis also showed no significant modifications. However, increased serum creatinine values were observed in some volunteers following suprofen administration. A drug relationship to this finding cannot be excluded with certainty. Two volunteers complained of nausea and vomiting following administration of two suprofen capsules. For this reason, volunteer no. 9 was withdrawn by the investigator from the study and replaced by an eligible substitute. In general, single doses of the two suprofen formulations investigated, were subjectively and objectively well tolerated. From the suprofen plasma-concentration time profiles, it was apparent that, whilst the elimination of suprofen was similar for both formulations, there was a marked delay in absorption of the tablet formulation. This formulation resulted in statistically significantly later maximum plasma levels and longer mean residence time (p less than 0.001). In comparison to the reference capsule formulation, the tablet had statistically significantly lower (75%) bioavailability. Measurement of suprofen concentrations in the urine indicated that less than 1% of the administered dose was excreted by this route.

Suprofen sustained release kinetics in healthy male volunteers. 2nd communication: a multiple dose steady-state kinetics of suprofen sustained release tablets during 6 days in healthy male volunteers.

To 12 healthy male volunteers, who had given their consent, 11 administrations of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) sustained release tablets 600 mg were given twice a day with a dosage interval of 12 h. It could be demonstrated that suprofen given as multiple dose application of sustained release tablets was well tolerated. Effective mean plasma levels were reached after the second dosage. There was no indication of accumulation nor accelerated elimination during the 6-day period. There was no statistically significant difference between the mean plasma curve after the last administration of the 6-day period and the mean plasma curve after the 3rd application. Also the AUC's in the respective intervals turned out not to be statistically significantly different from each other. Clinical and laboratory tests showed no clinically relevant deviations from the normal range. No adverse reactions whatsoever were observed.

Pharmacokinetics and tolerability of suprofen. Experience with intramuscular application in healthy volunteers.

In the present randomized single-blind study local and systemic tolerability of alpha-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol) 200 mg/ml i.m. were compared with those of diclofenac 25 mg/ml and placebo. The three treatment groups consisted of 15 patients each and were homogeneous with respect to demographic parameters. The volunteers were assigned to these groups in random fashion and underwent treatment with 3 injections/day of either suprofen or diclofenac or placebo for 7 days. Mild local pain or systemic intolerance signs were equally rare in all three groups. The laboratory tests with the three preparations studied failed to indicate any negative influence on the hematopoietic organs or the adrenal activity. Abnormal changes in the ECG and the cardiovascular parameters during the treatment were not observed. Moderately or slightly elevated SGOT and SGPT values were seen during treatment with suprofen; however, these values returned to normal after the treatment. As compared with these elevations the values for subjects on diclofenac were higher and did not return to normal within 5 days following withdrawal of the drug. Moreover, the creatine phosphokinase activity, observed in both the suprofen and the diclofenac group, was so extremely high in subjects on diclofenac that this drug had to extremely high in subjects on diclofenac that this drug had to be withdrawn on day 4 of the study. On the basis of these results it can be stated that intramuscular injections of suprofen 200 mg/ml are locally and systemically well tolerated even on administration t.i.d. Measurement of the steady-state plasma level was not indicative of altered kinetic behaviour of suprofen. The plasma levels remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Local and systemic tolerability of suprofen. Experience with intravenous administration and infusion in healthy volunteers (1st comm.).

Local and systemic tolerability of alpha-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol 200 mg/ml intravenous injection and suprofen 200 mg/ml infusion were in the present single-blind crossover study assessed and compared with those of placebo i.v. 12 volunteers each were in random fashion assigned to one of the three treatment groups; for a period of 7 days the subjects received daily 2 intravenous injections or infusions of suprofen or placebo, respectively. Investigator and patients appreciation of local tolerability revealed that no pain or discomfort occurred in 98% of the subjects on suprofen and in 100% of those on placebo. The incidence of limited, moderate or mild, adverse reactions was in the suprofen group higher than in the placebo group. The laboratory tests for the treatment groups indicated no negative effects on either the hematopoietic organs or the liver function; no abnormal changes in ECG and cardiovascular parameters were observed during the treatment period. Tests of the renal parameters, i.e., creatinine clearance, creatinine, and urea (BUN), revealed negative shifts in the first two parameters, whereas BUN remained uninfluenced. On the basis of these results it can be stated that 200 mg/ml of suprofen, given either as intravenous injection or as infusion, were both locally and systemically well tolerated even on administration b.i.d. The more or less unfavorable shifts in the renal parameters, which occurred with placebo as well as with suprofen, require further investigation.

Local and systemic tolerability of suprofen. Experience with intravenous administration and infusion in healthy volunteers (2nd comm.).

12 healthy male volunteers who had given consent to the study each received in a randomized cross-over design 13 applications of 2-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol) injection solution 200 mg/ml at 8 a.m. and at 2 p.m. as i.v. bolus injections or as infusions. It could be demonstrated, that suprofen given as multiple dose i.v. bolus injections or as multiple infusion doses was well tolerated. The peak plasma concentrations after i.v. bolus injections were in the range of 16.3 to 42.3 micrograms/ml (mean 26.5) and after 2 h between 1.3 and 9.8 micrograms/ml (mean 3.2). 1.5 h after the start of infusion (end of the infusion) the plasma concentrations were in the range of 4.0 and 11.2 micrograms/ml (mean 7.2) with a infusion rate of 4.6 mg/min for the first 30 min and then of 1.1 mg/min for about 57 additional min. At 2.5 h after the infusion applications the mean plasma level was 2.0 micrograms/ml. There was no indication of accumulation nor accelerated elimination during the 7-day period. There was no statistically significant difference between the plasma elimination after the last injection of the 7-day period and the plasma elimination after i.v. single injection as well as from the elimination after the last infusion of the 7-day period.

Pharmacokinetics and bioavailability of suprofen injection solution after intravenous application versus capsules on six healthy male volunteers.

In a three-way cross-over study six healthy male volunteers received intravenously 50 mg and 100 mg suprofen as a bolus injection and orally 200 mg as one capsule. The plasma level curves could be fitted to a two-compartimental model by means of the computer program NONLIN. The pharmacokinetic parameter estimates did not show dose dependency. The absolute bioavailability of suprofen taken as one capsule was 92.2% based on AUC-values and did not indicate a first-pass effect. The plasma input curve was determined by point-area deconvolution. Assuming first order input a half-life of 23 min could be derived based on point-area deconvolution. Different dissolution models based on USP XX are discussed in relation to the kinetic data generated.

Continuous body fluid monitoring for zomepirac by fully automated high-performance liquid chromatography.

A sensitive, specific and rapid determination of 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid sodium salt dihydrate (zomepirac sodium, Zomax) in human plasma and urine by a continuous body fluid monitoring system based on high-performance liquid chromatography is described. Samples are directly injected into the apparatus which consists of commonly available HPLC-modules. Manual sample clean-up procedures as well as the addition of an internal standard are not needed. Using 50-microliter aliquots, the detection limit is lower than 0.05 microgram/ml and the calibration ranges from 0.5 to 100 micrograms/ml are linear for both, spiked samples and references. The recovery is 97% for plasma and 95% for urine samples at a sampling rate of about 15 samples/h.

Stability indicating HPLC-method for the determination of econazole nitrate in cream and lotion formulations.

A simple, fast HPLC-method for the determination of econazole nitrate in cream (Pevaryl, Pevisone) and lotion formulations (based on polyethylenic oleic glycerides and mono/di-stearic esters of ethylene- and polyethylene glycol) is described. The method is stability indicating as well as linear (range 5-15 mg econazole nitrate/g) and shows a good recovery (98.7-100.2%) and a good reproducibility (cv less than 1%, n = 10). The chromatographic separation is achieved on a RP-18 column using methanol/aqueous ammoniumcarbonate solution/tetrahydrofurane as the mobile phase. Quantification of the chromatograms is done by internal standard method using peak areas.

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.

Quantitative determination of suprofen in human plasma and urine by fully automated high-performance liquid chromatography.

A sensitive, specific and rapid determination of suprofen in human plasma and urine by fully automated high-performance liquid chromatography is described. Plasma or urine samples are directly injected into the liquid chromatograph, which consists of commonly available modules. Manual sample cleanup procedures as well as the addition of an internal standard are not needed. Using 20 microliter-aliquots, the detection limit is lower than 0.05 microgram/ml and the calibration ranges from 1.0 to 100 micrograms/ml are linear for both, spiked samples and references. The recovery is 99.2% for plasma and 99.7% for urine samples.