Bioavailability of topical meloxicam gel.

摘要

Meloxicam (MLX) is a nonselective, nonsteroidal, anti-inflammatory drug (NSAID) with preferential inhibition of cyclo-oxygenase-2 (COX-2) over COX-1. MLX doesn't have documented cardiovascular toxicity at doses of less or equal to 15 mg/day which are recommended for the treatment of rheumatoid arthritis and osteoarthritis. It is also used in treatment of juvenile arthritis in children of at least two years of age. However, when orally administered it may cause severe side effects at the gastrointestinal level and can even reduce the life expectancy of patients with rheumatoid arthritis. Transdermal delivery of MLX would avoid major gastrointestinal side effects.;The purpose of this study was to quantify the systemic bioavailability of meloxicam in a rabbit model resulting from the application of 0.3% MLX gels with and without 5% menthol and 1% oleic acid. Preliminary work done in our laboratory showed that in vitro menthol and oleic acid are excellent penetration enhancers for MLX. Seven and one half grams of the gels were applied on an area of 7.5 x 7.5 cm on the previously shaved dorsum of three female rabbits (n=3). Animals were shaved 12 hours before the experiments. A short IV-infusion of 1 mg of MLX over 5 min was also administered on separate occasions. In each experiment, blood samples were collected serially for 36 hours and plasma was analyzed by a validated HPLC method. The HPLC method consisted of a reverse phase column C18, a flow rate of 0.8 ml/min, a mobile phase of methanol: water: phosphoric acid (59.9: 40: 0.1) and a detection wavelength of 370nm.;All the experiments were repeated 3 times. Plasma data were analyzed by non compartmental pharmacokinetic analysis. Fraction of drug absorbed for gels (F) was calculated as the ratio between the dose-normalized AUCs of gel and infusion. Dose absorbed from a gel application was calculated as (F*Dose gel).;Rabbits well tolerated the treatments. AUC in mug/mL/hr were: 4.5 +/- 1.1; 1.3 +/- 0.3; 19.8 +/- 9.6; and 6.3 +/- 0.7 for the infusion, the control-gel, the menthol-gel and the oleic acid-gel respectively. T max in hours were: 0.084; 18 +/- 3; 6.3 +/- 1.3 and 14 +/- 3.1 for the infusion, the control-gel, the menthol-gel and the oleic acid-gel respectively. Cmax in mug/ml were: 0.87 +/- 0.05, 0.07 +/- 0.02, 1.86 +/- 0.85 and 0.34 +/- 0.3 for the infusion, the control-gel, the menthol-gel and the oleic acid-gel respectively.;The presence of menthol increases the exposure of meloxicam up to 10-16 folds and the presence of oleic acid increases the exposure of meloxicam up to 3-6 folds. The rate of absorption also increased compared to the control-gel. Plasma concentrations of meloxicam were observed within one hour for the menthol-gel and the oleic acid-gel whereas it took at least 8 hours for control-gel to produce detectable concentrations. The menthol-gel delivered 0.95 +/- 0.22 mg/kg of MLX; the oleic acid-gel delivered 0.32 0.05 mg/kg of MLX versus the 0.063 +/- 0.017 mg/kg of MLX the control-gel. These results confirm what observed in-vitro that 5% menthol-gel and 1% oleic acid-gel may deliver therapeutically relevant doses of MLX.