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

Authors Goo YT, Sa CK, Choi JY, Kim MS, Kim CH, Kim HK, Choi YW

Received 23 December 2020

Accepted for publication 23 January 2021

Published 17 February 2021 Volume 2021:16 Pages 1245—1259


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Thomas J. Webster

Yoon Tae Goo,1,* Cheol-Ki Sa,1,* Ji Yeh Choi,2 Min Song Kim,1 Chang Hyun Kim,1 Hyeon Kyun Kim,1 Young Wook Choi1

1College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; 2Department of Psychology, York University, Toronto, Ontario, Canada

*These authors contributed equally to this work

Correspondence: Young Wook Choi
College of Pharmacy, Chung-Ang University, 84 Heuksuk-Ro, Dongjak-Gu, Seoul, 06974, Korea
Tel +82 2 820 5609

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: revaprazan, supersaturation, solid micelle, Box-Behnken design, dissolution, oral bioavailability

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