A Novel Slowly Self‐Emulsifying Drug Delivery System: Prolonged Systemic Exposure of Tacrolimus With Reduced Risks of Systemic Side Effects

This study aimed to design and characterize a new type of self‐emulsifying drug delivery system (SEDDS), slowly SEDDS (SL‐SEDDS), for long‐lasting systemic exposure of tacrolimus (TAC) with reduced nephrotoxicity. TAC‐loaded SL‐SEDDS (SL‐SEDDS/TAC) was prepared by semi‐solidifying TAC‐loaded SEDDS (SEDDS/TAC) composed of Capryol 90, Cremophor EL, and polyethylene glycol 400 with Geleol. SEDDS samples were evaluated regarding physicochemical and biopharmaceutical properties. Both SEDDS/TAC and SL‐SEDDS/TAC formed fine emulsions in water. The dissolution of SEDDS/TAC reached approximately 100% within the initial 30 min in simulated gastric fluid (SGF), and the SL‐SEDDS/TAC samples exhibited slower dissolution than SEDDS/TAC in a Geleol content‐dependent manner. SL‐SEDDS/TAC with a Geleol content of 17.5 wt% showed 25% dissolution in SGF for 2 h, followed by an additional 31% dissolution in simulated intestinal fluid for 10 h. The sample was selected as a favorable SL‐SEDDS/TAC for further studies because of its slow and continuous dissolution. Oral SEDDS/TAC and the selected SL‐SEDDS/TAC (10 mg‐TAC/kg) offered almost identical bioavailability of 18% and 19%, respectively, in rats. Compared with SEDDS/TAC, SL‐SEDDS/TAC achieved a 32% decrease in the maximum plasma concentration, a risk factor of nephrotoxicity, from 383 to 262 ng/mL with significantly prolonged mean residence time. In a rat model of acute kidney injury, SL‐SEDDS/TAC (10 mg‐TAC/kg/day, 3 days) attenuated the elevation of blood nitrogen urea by 33% compared to SEDDS/TAC, suggesting a reduction in nephrotoxic risks. SL‐SEDDS could be a promising dosage form to control oral absorption of TAC for effective and safe medication.