In order to improve water solubility of a lipophilic drug, tacrolimus (FK506), two prodrugs (FK506-G or FK506-S) such as FK506-M32-LS-G (FK506-G) and FK506-M32-LS-SL (FK506-S) were synthesized. Two prodrugs (FK506-G or FK506-S), including FK506, were characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), scanning electron microscopy (SEM), enzymatic kinetics, and cytotoxicity. A phase solubility test was conducted in distilled water, and the solubility of two prodrugs (FK506-G or FK506-S) was measured in various pH values for pH solubility profiles. Most interesting was that FK506-S showed the highest solubility, 866 μg/mL in water. In vitro enzymatic kinetics of two prodrugs (FK506-G or FK506-S) in human plasma was evaluated by measuring the decrease of FK506-G or FK506-S as well as the increase of FK506 by HPLC, and FK506-G or FK506-S was metabolized in 1 h in human plasma. Two prodrugs (FK506-G or FK506-S) including FK506 showed an IC50 of 336.6 μg/mL for FK506, 337.9 μg/mL for FK506-G, or 480.1 μg/mL for FK506-S against a conjunctive cell line, Clone 1-5c-4 cells. Taken together, FK506-S could be the most optimal prodrug for aqueous preparations based on preformulation data.
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