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; X₁) and the amounts of Florite PS-10 (FLO; X₂) and Vivapur 105 (VP105; X₃), and three response variables, ie, dissolution efficiency at 30 min (Y₁), dissolution enhancing capacity (Y₂), and Carr's index (Y₃). 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 X₁ (-0.41), X₂ (0.31), and X₃ (-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 Y₁ (40.3%), Y₂ (0.008), and Y₃ (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.

Keywords: Box-Behnken design; dissolution; oral bioavailability; revaprazan; solid micelle; supersaturation.

Figure 1

Solubility of RVP in various surfactant solutions (1% [w/w]) (A) and CMC determination via the solubilization method (B).

Figure 2

Dissolution profiles of micelle with or without various supersaturating agents.

Figure 3

Plots of the CI against the ratio of solid carrier to SuM to evaluate flow property changes in SuM formulations with silica-based adsorbents (A) and cellulose-based diluents (B).

Figure 4

Effects of independent factors on response variables: three-dimensional response surface plots of Y₁ (A), Y₂ (B), and Y₃ (C).

Figure 5

Solid-state properties of powders. (A) Scanning electron microscopy images. (B) Differential scanning calorimetry thermograms. (C) Powder X-ray diffractometry patterns.

Figure 6

Dissolution profiles of raw RVP, Revaprazan^® (powder), solid micelle, and the optimized SSuM in distilled water.

Figure 7

Plasma RVP concentration profiles after oral administrations of different formulations to Sprague-Dawley rats at an equivalent dose of 20 mg/kg of RVP.