The in vitro release profiles and the
bleeding phenomenon of
Tacrolimus and
propylene carbonate (PC) as a dispersing
solvent for
Tacrolimus drug substance in
Tacrolimus ointment were investigated when changing concentrations of
Tacrolimus and PC in the
ointment were used, respectively. The
bleeding test result indicated that
Tacrolimus was in equilibrium between inside and outside of PC droplets in intact
ointment base. A cumulative release amount of
Tacrolimus from
ointment, plotted against the square root of time, showed a straight line initially with a slope of q1 followed to change a slope to be q2 at a certain time, where the relation of these slopes being q1<q2. The q1 values increased with the concentration of
Tacrolimus but decreased with PC concentration in
Tacrolimus ointment. And the q2 values increased with
Tacrolimus concentration but were independent of PC concentration. These profiles indicated that there were two phases for
Tacrolimus release from
ointment, namely, first phase was related with the period during PC release and the second phase was related with the state of
ointment after PC release. When the PC release was applied to the Higuchi's release equation, the above slope q1 was found to be correlated to the parameter of A/phi(0), where A was a parameter of release rate of PC and phi(0) was an initial volume fraction of PC droplets. It should be indicated that more rapid release rate of PC rather than that of
Tacrolimus resulted in the generation of amorphous phase of
Tacrolimus outside of remaining PC droplets. During PC release, the slope q1 could be influenced by the thermodynamic activity of
Tacrolimus dissolved in PC droplets. After PC release, it would be reasonable to speculate that the amorphous cluster of
Tacrolimus with a constant thermodynamic activity would give constant q2 values regardless of PC contents in
Tacrolimus ointment.