ABSTRACT
A specific and accurate reversed-phase HPLC with UV detection was developed for the assay of atorvastatin in beagle dog plasma. Indomethacin was used as the internal standard. Atorvastatin was extracted by protein precipitation, the extracts were injected into a Kromasil C8 column (150 mm x 4.6 mm, 5 microm) with UV wavelength set at 270 nm. The mobile phase consisted of acetonitrile:0.1 mol/L ammonium acetate buffer (pH 4.0) (65:35% v/v) at a flow rate of 1.0 ml/min. The column was at ambient temperature (25 degrees C). The injection volume was 25 microl. The blank plasma did not interfere with the determination of atorvastatin and indomethacin. A good linear relationship was obtained between the peak area ratio of atorvastatin to indomethacin and the concentration of atorvastatin over the range of 0.05 to 2.5 microg/mL. The limit of quantification was 25 ng/mL, the limit of detection was 8 ng/ml. The total chromatographic analysis time was within 9 min. The method is accurate, precise and fast for the assay of atorvastatin in plasma following oral administration of an atorvastatin SMEDDS to healthy beagle dogs.
Subject(s)
Heptanoic Acids/administration & dosage , Heptanoic Acids/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Pyrroles/administration & dosage , Pyrroles/pharmacokinetics , Animals , Atorvastatin , Chromatography, High Pressure Liquid , Dogs , Drug Delivery Systems , Emulsions , Indicators and Reagents , Male , Reproducibility of Results , Spectrophotometry, UltravioletABSTRACT
AIM: To prepare self-microemulsifying drug delivery system (SMEDDS) containing atorvastatin,and decrease its size to improve the solubility in the stomach. And to study the effect of the resultant microemulsion in reducing the presystemic clearance in the gastrointestinal mucosa and hepatic first-pass metabolism, improving the oral bioavailability, and reducing side effect and expenditure. METHODS: Pseudoternary phase diagrams were used to evaluate the self-microemulsification existence area. The HPLC analyses in vitro and in vivo were set up. Solubility in various vehicles was determined. The self-microemulsification efficiency was assessed, such as self-microemulsification time, stability, particle size and zeta potential. SMEDDS containing atorvastatin, non-ionic surfactant and lipid were prepared. Droplet size/distributions and zeta potential of the resultant microemulsion were determined. Photos were taken with transmission electron microscope. Oral bioavailability was studied on prepared SMEDDS hard capsules and compared with that of the conventional tablet in Beagle dogs in vivo. RESULTS: The optimal formulations had wide microemulsion existent field and had good self-microemulsifying efficiency. Droplet size was within 100 nm and showed Gaussian distribution. After oral administration of SMEDDS capsules and the conventional tablet to fasted Beagle dogs, the Cmax from SMEDDS was greater than that of the conventional tablet. AUC from zero to 24 h of SMEDDS was about 1.5-fold higher than that of the conventional tablet. Oral bioavailability of atorvastatin SMEDDS was greater than that of the conventional tablet. CONCLUSION: The results indicated the potential use of SMEDDS for the delivery of atorvastatin to increase its oral bioavailability.
