UniORV, a New Multi-Unit Dosage Form, Improved Biopharmaceutical Properties of Tacrolimus in Rats and Humans

Purpose The aim of the present study was to develop a new multi-unit dosage formulation, Universal ORbicular Vehicle (UniORV), to improve the biopharmaceutical properties of tacrolimus (TAC). Methods TAC-loaded UniORV (UO/TAC) was produced by the dripping and gelling of a solution comprising TAC, gelatin, starch syrup, and triethyl citrate at 0.5 w /w% drug loading. Its microstructure was elucidated by polarized light microscopy and the Raman mapping technique. The pharmacokinetic profiles of TAC after the oral administration of UO/TAC were evaluated in rats and healthy humans. Results The dissolution behavior of UO/TAC was similar to that of commercial capsules, and the formation of nanoparticles was detected by TEM in dissolved media. In a stability study on UO/TAC, only 2.6 and 4.7% decreases in TAC concentrations were observed at 40± 2°C/75 ± 5% relative humidity for 4 months and at 50± 2°C for 2 months, respectively. A pharmacokinetic study on rats revealed a 30-fold higher AUC than that with crystalline TAC. A randomized double-blind crossover study on 8 healthy males showed that UniORV achieved a 1.4-fold increase in AUC and 34% decrease in inter-individual variation from the reference formulation. Conclusion The new dosage form UniORV is a promising approach to improve the dissolution, amorphous stability, and biopharmaceutical properties of TAC, which is a poorly water-soluble drug.