How do in-vitro release profiles of nanosuspensions from Alzet® pumps correspond to the in-vivo situation? A case study on radiolabeled fenofibrate.
The absorption characteristics and kinetics of practically water-insoluble drugs following subcutaneous injection of their aqueous suspensions were investigated in intact rats by the local clearance method and compared with those following intramuscular injection reported previously. The plot of the cube root of the residual fraction of the drug in the injection site versus time gave a good linear relationship under various experimental conditions. The absorption rate constant (j) increased with decreasing particle size. This increase was remarkable in the region of mean particle diameter less than 2-3 micrometers, while it was gradual or slight in the region above this. This phenomenon was explained by the fact that the in vivo spreading of particles of more than approximately 3 micrometers was still more limited by the network of the fibrous tissues. Between j and the initial drug concentration (C0) or injection volume (V0), the practically important relationship j alpha C0g V0h (g = -0.66 and h = -0.32) could approximately be derived from the experimental results. Comparison of j values among various compounds with different solubility (C's) in saline but with similar colloidal properties (particle size distribution and sedimentation volume) showed that a log j versus log C's plot gave a nearly straight line with a slope of approximately 0.5. All the results observed for the subcutaneous absorption were similar to those for intramuscular absorption and could reasonably be explained by the kinetic model proposed for intramuscular absorption.