Development of a Solid Supersaturable Micelle of Revaprazan for Improved Dissolution and Oral Bioavailability Using Box-Behnken Design

Abstract

Purpose

To enhance the oral bioavailability of revaprazan (RVP), a novel solid, supersaturable micelle (SSuM) was developed.

Methods

Surfactants and solid carriers were screened based on a solubility and a flowability test, respectively. Supersaturating agents, including Poloxamer 407 (P407), were screened. The SSuM was optimized using a Box-Behnken design with three independent variables, including Gelucire 44/14:Brij L4 (G44/BL4; X ₁) and the amounts of Florite PS-10 (FLO; X ₂) and Vivapur 105 (VP105; X ₃), and three response variables, ie, dissolution efficiency at 30 min (Y ₁), dissolution enhancing capacity (Y ₂), and Carr’s index (Y ₃). The solid state property was evaluated, and a dissolution test was conducted. RVP, Revanex ^®, solid micelle (P407-free from the composition of SSuM), and SSuM were orally administrated to rats (RVP 20 mg equivalent/kg) for in vivo pharmacokinetic study.

Results

G44 and BL4 showed great solubility, with a critical micelle concentration range of 119.2–333.0 μg/mL. P407 had an excellent supersaturating effect. FLO and VP105 were selected as solid carriers, with a critical solidifying ratio (g/mL) of 0.30 and 0.91, respectively. With optimized values of X ₁ (–0.41), X ₂ (0.31), and X ₃ (–0.78), RVP (200 mg)-containing SSuM consisting of G44 (253.8 mg), BL4 (106.2 mg), FLO (99.3 mg), VP105 (199.8 mg), and P407 (40 mg) was developed, resulting in Y ₁ (40.3%), Y ₂ (0.008), and Y ₃ (12.3%). RVP existed in an amorphous state in the optimized SSuM, and the SSuM formed a nanosized dispersion in the aqueous phase, with approximately 71.7% dissolution at 2 h. The optimized SSuM improved the relative bioavailability of RVP in rats by approximately 478%, 276%, and 161% compared to raw RVP, Revanex ^®, and solid micelle, respectively.

Conclusion

The optimized SSuM has great potential for the development of solidified formulations of poorly water-soluble drugs with improved oral absorption.