Optimization of a solidified micelle formulation for enhanced oral bioavailability of atorvastatin calcium using statistical experimental design

Abstract

To enhance the oral bioavailability of atorvastatin calcium (ATV), a novel solidified micelle (S-micelle) was developed. Two surfactants, Gelucire 48/16 (G48) and Tween 20 (T20), were employed for micelle formation, and two solid carriers (SC), Florite PS-10 (FLO) and Vivapur 105 (VP105), were selected as solid carriers. The S-micelle was optimized using a Box-Behnken design with three independent variables, including G48:T20 (X₁, 1.8:1), SC:G48 + T20 (X₂, 0.65:1), and FLO:VP105 (X₃, 1.4:0.6), resulting in a droplet size (Y₁) of 198.4 nm, dissolution efficiency at 15 min in the pH 1.2 medium (Y₂) of 47.6%, Carr's index (Y₃) of 16.9, and total quantity (Y₄) of 562.5 mg. The optimized S-micelle resulted in good correlation showing percentage prediction values less than 10%. The optimized S-micelle formed a nanosized dispersion in the aqueous phase, with a higher dissolution rate than raw ATV and crushed Lipitor®. The optimized S-micelle improved the relative bioavailability of oral ATV (25 mg equivalent/kg) in rats by approximately 509 and 271% compared to raw ATV and crushed Lipitor^®, respectively. In conclusion, the optimized S-micelle possesses great potential for the development of solidified formulations for improved oral absorption of poorly water-soluble drugs.

Keywords: Atorvastatin calcium; Box-Behnken design; Gelucire 48/16; dissolution; oral bioavailability; solidified micelle.