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
• Gelucire 48/16
• solidified micelle
• Box-Behnken design
• dissolution
• oral bioavailability

Acknowledgement

We thank Gattefossé for financial support.

Author contributions

YTG and Y-HW: methodology and writing the original draft. SHH: formulation and in vitro dissolution. JYC: statistical analysis. GHS: solid state characterization. CHK and HMJ: Assistance of in vivo PK study. YWC: conceptualization, methodology, supervision, and original draft editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported in part by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2022R1A2B5B02001794].