Studies on the absorption of practically water-insoluble drugs following injection. II. Intramuscular absorption from aqueous suspensions in rats

The absorption characteristics and kinetics of practically water-insoluble drugs following intramuscular injection of their aqueous suspensions were investigated by the local clearance method in the m. gastrocnemius of the rat. The plot of the cube root of the residual fraction of the drug in the injection site versus time gave a good straight line. Between the absorption rate constant (j) and the initial drug concentration (C0) or injection volume (V0), the relationship jvC0g V0h was observed experimentally (g=-0.55 and h=-0.32). Comparison of j values among various compounds having different solubilities in saline (Cs') but similar colloidal properties (particle size distribution and sedimentation volume) showed that a plot of log j against log Cs'gave a linear relationship with a slope close to 0.5. The absorption rate constant (j) increased with decreasing particle size on condition that the other colloidal properties changed little. This increase was remarkable in the region of mean particle diameter (Dss) less than 2-3 μm, while it was gradual or slight in the region above this. The results could be explained by a kinetic model in which the dissolution (diffusion) process from the particle agglomerate formed by injection was assumed to be a rate-limiting step for the drug absorption. The effect of the type or concentration of the macromolecular dispersing agent was also examined in detail.