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

Abstract

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.