fumarates and montelukast

To develop a montelukast sodium-loaded stable oral suspension bioequivalent to the commercial granules in rats, several montelukast sodium-loaded suspensions were prepared with a suspending agent, stabilizers and anti-aggregation agents, and their stabilities were investigated by visually observing the sedimentation phenomenon and determining the concentration of the degradation product. Moreover, dissolution and pharmacokinetic studies of the optimized formulation were examined in rats compared to commercial montelukast sodium-loaded granules. Avicel RC-591 (Avicel), a suspending agent, prevented the sedimentation of these suspensions at >2.496 (w/v) per cent composition. Amongst the stabilizers tested, fumaric acid provided the lowest concentration of montelukast sulphoxide (a degradation product) in these suspensions at 40 °C, demonstrating its excellent stabilizing activity. Furthermore, as an anti-aggregation agent, glycerin gave lower amounts of degradation product than those with poloxamer 407 and Tween 80. In particular, montelukast-loaded oral suspension, an aqueous suspension containing montelukast sodium/Avicel/fumaric acid/glycerin at a concentration of 312/2496/15.6/62.4 (mg/100 ml), and the commercial granules exhibited similar dissolution profiles in 0.5% (w/v) aqueous solution of sodium lauryl sulphate. Moreover, the pharmacokinetics in rats provided by this suspension was comparable to that of the commercial granules, suggesting that they were bioequivalent. In addition, it was physically and chemically stable at 40 °C for at least 6 months. Thus, this montelukast sodium-loaded oral suspension, with bioequivalence to the commercial granules and excellent stability, could be a prospective dosage form for the treatment of asthma.

Topics: Acetates; Administration, Oral; Animals; Anti-Asthmatic Agents; Cellulose; Cyclopropanes; Drug Stability; Excipients; Fumarates; Glycerol; Male; Quinolines; Rats, Sprague-Dawley; Solubility; Sulfides; Suspensions; Technology, Pharmaceutical; Therapeutic Equivalency

A nonsynonymous single nucleotide polymorphism (SNP) in the SLCO2B1 gene encoding organic anion transporting polypeptide 2B1 (OATP2B1), c.935G>A (p.R312Q; rs12422149), has been associated with reduced plasma concentrations of montelukast in patients with asthma. Our aim was to examine the possible effects of the SLCO2B1 c.935G>A SNP on the single-dose pharmacokinetics of the suggested OATP2B1 substrates montelukast and aliskiren.. Sixteen healthy volunteers with the SLCO2B1 c.935GG genotype, 12 with the c.935GA genotype, and five with the c.935AA genotype ingested a single 10 mg dose of montelukast or a 150 mg dose of aliskiren, with a washout period of 1 week. Plasma montelukast concentrations were measured up to 24 h. Plasma and urine aliskiren concentrations were measured up to 72 and 12 h, respectively, and plasma renin activity up to 24 h after aliskiren intake.. The SLCO2B1 genotypes had no significant effect on the pharmacokinetics of montelukast or aliskiren. The geometric mean ratios with 90% confidence intervals of montelukast area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) in participants with the c.935GA or the c.935AA genotype to those with the c.935GG genotype were 1.02 (0.87, 1.21) or 0.88 (0.71, 1.10), respectively (P=0.557). The geometric mean ratios (90% confidence interval) of aliskiren AUC(0-∞) in participants with the c.935GA or the c.935AA genotype to those with the c.935GG genotype were 0.98 (0.74, 1.30) or 1.24 (0.85, 1.80), respectively (P=0.576).. These data do not support the suggested functional significance of the SLCO2B1 c.935G>A SNP on OATP2B1 activity in vivo.

Topics: Acetates; Adult; Amides; Antihypertensive Agents; Chromatography, Liquid; Cross-Over Studies; Cyclopropanes; Female; Fumarates; Genotype; Humans; Leukotriene Antagonists; Male; Middle Aged; Organic Anion Transporters; Polymorphism, Single Nucleotide; Quinolines; Radioimmunoassay; Renin; Sulfides; Tandem Mass Spectrometry; Tissue Distribution; Young Adult