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

• Published in: International journal of nanomedicine Vol. 16; pp. 1245 - 1259
• Main Authors: Goo, Yoon Tae, Sa, Cheol-Ki, Choi, Ji Yeh, Kim, Min Song, Kim, Chang Hyun, Kim, Hyeon Kyun, Choi, Young Wook
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2021; Taylor & Francis Ltd; Dove; Dove Medical Press
• Subjects: Administration, Oral; Animals; Bioavailability; Biological Availability; box-behnken design; Cellulose; dissolution; Drug Compounding; Drug delivery systems; Drugs; Equilibrium; Laboratory animals; Male; Membrane filters; Micelles; Models, Theoretical; oral bioavailability; Original Research; Particle Size; Pharmaceuticals; Polyethylene Glycols; Pyrimidinones - pharmacokinetics; Pyrimidinones - pharmacology; Rats; Rats, Sprague-Dawley; revaprazan; solid micelle; Solubility; Solutions; supersaturation; Surface active agents; Surface-Active Agents - chemistry; Surfactants; Tetrahydroisoquinolines - pharmacokinetics; Tetrahydroisoquinolines - pharmacology; South Korea; Japan; Germany; United States > US; revaprazan; Box-Behnken design; oral bioavailability; supersaturation; dissolution; solid micelle
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S298450

To enhance the oral bioavailability of revaprazan (RVP), a novel solid, supersaturable micelle (SSuM) was developed. 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 ) and the amounts of Florite PS-10 (FLO; X ) and Vivapur 105 (VP105; X ), and three response variables, ie, dissolution efficiency at 30 min (Y ), dissolution enhancing capacity (Y ), and Carr's index (Y ). 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. 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 (-0.41), X (0.31), and X (-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 (40.3%), Y (0.008), and Y (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. The optimized SSuM has great potential for the development of solidified formulations of poorly water-soluble drugs with improved oral absorption.