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Abstract:A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) of cyclosporine A (CyA)-a poorly water-soluble immunosuppressant-was constructed in order to attain an apparent concentration-time profile comparable to that of conventional SEDDS with reduced use of oil, surfactant, and cosolvent. Several hydrophilic polymers, including polyvinylpyrrolidone (PVP), were employed as precipitation inhibitors in the conventional SEDDS, which consists of corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil, ethanol, and propylene glycol. PVP-incorporated pre-concentrate (CyA:vehicle ingredients:PVP = 1:4.5:0.3 w/v/w) spontaneously formed spherical droplets less than 120 nm within 7 min of being diluted with water. In an in vitro dialysis test in a biorelevant medium such as simulated fed and/or fasted state intestinal and/or gastric fluids, PVP-based S-SEDDS exhibited a higher apparent drug concentration profile compared to cellulose derivative-incorporated S-SEDDS, even displaying an equivalent concentration profile with that of conventional SEDDS prepared with two times more vehicle (CyA:vehicle ingredients = 1:9 w/v). The supersaturable formulation was physicochemically stable under an accelerated condition (40 • C/75% RH) over 6 months. Therefore, the novel formulation is expected to be a substitute for conventional SEDDS, offering a supersaturated state of the poorly water-soluble calcinurin inhibitor with a reduced use of vehicle ingredients.

A new Soluplus (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion <70 nm in size when in contact with aqueous medium. In an in vitro dissolution test in a nonsink condition, the amphiphilic polymer noticeably retarded drug precipitation and maintained >80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different ( P >0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients.

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