Bioavailability of two oral-tablet and two oral-suspension formulations of naproxen sodium/paracetamol (acetaminophen): single-dose, randomized, open-label, two-period crossover comparisons in healthy Mexican adult subjects.

BACKGROUND: Naproxen sodium/paracetamol (acetaminophen) is a combination for the treatment of symptomatic pain and fever marketed both as a prescription and an over-the-counter product in Mexico. OBJECTIVE: The aim of these 2 studies was to compare the bioavailability and to determine the bioequivalence of 2 test formulations (an oral-tablet formulation containing the combination of naproxen sodium/paracetamol 275/300 mg and an oral-suspension formulation containing the combination of naproxen sodium/paracetamol 375/300 mg per 15 mL) with their corresponding listed reference-drug formulations in Mexico (a list issued by Mexican health authorities). METHODS: Two separate, single-dose, randomized, open-label, 2-period crossover, postmarketing studies were conducted. For each study, a different set of eligible subjects was selected comprising healthy Mexican adults of either sex, and subjects were randomly assigned to receive 1 test formulation of the combination of naproxen sodium/paracetamol followed by the corresponding reference-drug formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour overnight fast, subjects received a single dose of naproxen sodium/paracetamol 275/300-mg tablet or naproxen sodium/paracetamol 375/300 mg per 15 mL suspension, depending on the study. For the analysis of pharmacokinetic parameters, including C(max), AUC from time 0 (baseline) to 48 hours (AUC(0-48)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline and at 0.16, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after administration. The formulations were considered bioequivalent if the geometric mean ratios (test/reference) of the C(max) and AUC were within the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, monitoring vital signs, laboratory analysis results, and subject interviews regarding adverse events. RESULTS: A total of 26 subjects (15 men, 11 women; mean [SD] age, 29 [8] years [range, 20-50 years]; weight, 63.1 [9] kg [range, 51.4-84.4 kg]; height, 164 [9] cm [range, 149-179 cm]; and body mass index [BMI], 23.53 [2.18] kg/m(2) [range, 18.54-26.82 kg/m(2)]) were enrolled to receive the suspension-dosage formulation; 13 subjects received the suspension-test formulation first. A total of 26 subjects (13 men, 13 women; mean [SD] age, 29 [8] years [range, 18-43 years]; weight, 64.3 [7.7] kg [range, 50.6-80.7 kg]; height, 165 [9] cm [range, 151-181 cm]; and BMI, 23.64 [2.43] kg/m(2) [range, 18.02-26.42 kg/m(2)]) were enrolled to receive the tablet-dosage formulation; 13 subjects received the tablet-test formulation first. No significant period or sequence effects were detected based on analysis of variance. For the suspension-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 93.06% to 104.00%, 93.50% to 98.44%, and 92.14% to 98.99%, respectively, and were 90.09% to 105.90%, 88.58% to 99.34%, and 91.43% to 101.55%, respectively, for paracetamol. For the tablet-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 102.83% to 117.15%, 96.59% to 104.26%, and 96.01% to 102.90%, respectively, and were 94.04% to 121.09%, 95.48% to 105.64%, and 96.64% to 105.42%, respectively, for paracetamol. CONCLUSIONS: In these 2 small studies in healthy Mexican adult subjects, a single dose of naproxen sodium/paracetamol 275/300 mg of the test formulation of the tablet-dosage formulation or a single dose of naproxen sodium/paracetamol 375/300 mg per 15 mL of the test formulation of the suspension-dosage formulation was found to be bioequivalent to the corresponding reference formulations according to the regulatory definition of bioequivalence based on the rate and extent of absorption. All formulations were generally well tolerated.

Development and validation of a high-performance thin-layer chromatographic method, with densitometry, for quantitative analysis of ketorolac tromethamine in human plasma.

Ketorolac tromethamine is a potent nonsteroidal anti-inflammatory drug that is widely used in the treatment of moderate to severe pain. A new method was developed and validated for quantifying ketorolac (the free acid of the tromethamine salt) in human plasma by high-performance thin-layer chromatography. The stationary phase was silica gel 60, and the composition of the mobile phase was n-butanol-chloroform-acetic acid-ammonium hydroxide-water (9 + 3 + 5 + 1 + 2, v/v). The densitometric analysis of ketorolac was performed at 323 nm. The method was validated for precision (repeatability and reproducibility), accuracy, and sensitivity. Repeatability was 10.11% [coefficient of variation (CV)] and reproducibility was 12.18% (CV) as the maximum variation. Accuracy was determined at 3 different concentration levels, and results were within +/-15% of the predetermined range. Data were fitted by a linear mathematical function (linear regression). The calibration graph was linear in the range of 200-2000 ng/mL. Average recovery was 73.67%. The method proved to be accurate, precise, and sensitive for the ketorolac tromethamine quantification.

Bioavailability of two sublingual formulations of ketorolac tromethamine 30 mg: a randomized, open-label, single-dose, two-period crossover comparison in healthy Mexican adult volunteers.

BACKGROUND: Ketorolac tromethamine (ie, ketorolac) is an NSAID that appears to have several mechanisms of action, including inhibition of prostaglandin synthesis, modulatory effect on opioid receptors, and nitric oxide synthesis. Ketorolac is used in the treatment of pain. There are various generic formulations of sublingual ketorolac available in Mexico. However, a literature search did not identify published data concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of this study was to compare the bioavailability of 2 sublingual formulations of ketorolac 30-mg tablets in healthy Mexican adult volunteers. METHODS: This was a randomized-sequence, open-label, single-dose, 2-period crossover (2 dosing periods x 2 treatments) study comparing the bioavailability of two 30-mg sublingual tablet formulations of ketorolac. Healthy Mexican adult (aged, 18-55 years) men and women were eligible for inclusion. Subjects were randomly assigned in a 1:1 ratio to receive a single dose of the test formulation or the reference formulation. After a 12-hour overnight fast, subjects received a single dose of the corresponding formulation. There was a 7-day washout period between administration periods. Plasma samples were obtained over a 24-hour period after administration. Plasma ketorolac concentrations were analyzed by high-performance liquid chromatography for analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity. Blood samples were drawn immediately after sublingual placement of the drug and at 10, 20, 30, 40, 50, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, 12, and 24 hours after dosing. The formulations were considered bioequivalent if the geometric mean ratios of Cmax and AUC were within the predetermined range of 80% to 125% and if P for the 90% CIs was <0.05. Tolerability was assessed by vital sign monitoring, laboratory analysis results, and subject interviews. RESULTS: A total of 27 subjects (18 women, 9 men; mean [SD] age, 27 [9] years [range, 18-47 years]; weight, 61 [8] kg [48-79 kg]; height, 163 [8] cm [150-180 cm]) were enrolled and completed the study. Fourteen subjects received the test formulation first. No period or sequence effect was observed. The 90% CIs for the corresponding differences in natural log Cmax, AUC0-24, and AUC0-infinity were 95.94% to 114.66%, 98.34% to 105.90%, and 99.25% to 108.36%, respectively (all, (P) < 0.05), meeting the predetermined criteria for bioequivalence. Sixteen subjects experienced a total of 20 adverse events (AEs) during the study. None of the AEs were considered serious. One AE (nausea) appeared to be related to use of the reference formulation. CONCLUSIONS: In this small study in 27 healthy Mexican adult volunteers, the test formulation of a single, 30-mg sublingual tablet of ketorolac appeared to be bioequivalent to the reference formulation based on the rate and extent of absorption. Both formulations were well tolerated.