Purpose Because of its biopharmaceutical issues, improvement in oral absorption of tacrolimus (TAC) has been desired.  The purposes of present study were (ⅰ) design on TAC formulation, (ⅱ) prediction of its pharmacokinetic (PK) behavior in rats, and (ⅲ) optimization in a self-micellizing solid dispersion (SMSD) of TAC for improvement in systemic exposure of TAC.

Method SMSD formulation of TAC with Soluplus^®, an amphiphilic copolymer, (SMSD/TAC) and amorphous solid dispersion (ASD) formulation of TAC with hydroxypropylcellulose (ASD/TAC) were prepared with freeze drying process.  Physicochemical properties of SMSD/TAC were characterized in terms of morphology, crystallinity, and micelle-forming potencies.  SMSD formulation was optimized according to outcome from in silico modeling and simulation (M&S) for prediction of PK behavior.  Oral absorption of SMSD/TAC in rats was predicted with use of M&S, and PK behavior was evaluated in rats.

Results TAC in both formulations was in an amorphous state.  Compared with other TAC samples, SMSD/TAC immediately formed fine micelles with a mean diameter of ca. 170-nm in water and exhibited significant improvement in dissolution behavior of TAC.  Result from the predicted plasma concentration of TAC from dissolution profile of SMSD/TAC was indicative of remarkable improvement in oral absorption of TAC in rats.  After oral administration of TAC samples (10 mg TAC/kg) in rats, low systemic exposure of crystalline TAC was observed with bioavailability (BA) of 0.6%.  In contrast, there was marked enhancement in systemic exposure of TAC in both ASD/TAC and SMSD/TAC; in particular, SMSD/TAC achieved increase in BA of ca. 20-fold higher than crystalline TAC.  Thus, predicted PK profile of TAC samples seemed to be in agreement with the observed PK profile.

Conclusion SMSD approach could be a beneficial dosage form for TAC as well as other poorly water soluble drugs to improve their biopharmaceutical properties.