Pharmacokinetics of ketorolac loaded to polyethylcyanoacrylate nanoparticles using UPLC MS/MS for its determination in rats

Abstract

Polyethylcyanoacrylate (PECA) nanoparticles (NPs) have been employed as biodegradable polymeric carriers for oral (PO) delivery of ketorolac. The nanoparticles were prepared by polymerization technique at room temperature in a continuous aqueous phase at pH 2.5. This polymerization technique was able to hold 76–96% of ketorolac and the drug loading was a monomer concentration dependent. The feasibility of PECA NPs as PO controlled drug delivery systems of ketorolac was investigated in two groups of rats which were given orally either ketorolac tromethamine solution (1.5 mg/kg) or the selected ketorolac NPs aqueous dispersion (1.6 mg/kg). Ketorolac plasma concentrations were measured by a new fully validated specific, precise and accurate ultra-performance liquid chromatography tandem mass spectrometry (UPLC MS/MS) assay. The detection was performed on Waters TQ detector via negative electrospray ionization in a multiple reaction monitoring mode. Linear response ( r 2 ≥ 0.995) was observed over the range of 10–10,000 ng/ml of ketorolac, with the lower limit of quantification of 5 ng/ml with 1 μl injection volume. The intra- and inter-day precision (relative standard deviation, R.S.D.) values were <10% and the accuracy (relative error) was ≤8 for ketorolac concentrations. The drug solution is rapidly absorbed, distributed, and eliminated and shows a monophasic elimination phase. The assay was sensitive to follow pharmacokinetics of ketorolac in rats up to 24 h after a PO dose of its aqueous solution or NPs suspension. After NPs administration the mean Cmax, 5.0 ± 1.3 mg/l, was attained at 1 h. The drug was successfully maintained around this elevated plasma drug concentration up to 6 h (>2 t 1/2), in rats. The AUC was significantly higher after the NPs suspension than the solution of ketorolac. This present study provides evidence that the sorption of ketorolac to PECA NPs could control the drug release/elimination in rats.