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. 2022 May 21:4:100119.
doi: 10.1016/j.ijpx.2022.100119. eCollection 2022 Dec.

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

Yuanyuan Meng  1   2 , Fangyun Tan  1   2 , Jiaxin Yao  1 , Yanan Cui  1 , Yumiao Feng  1   3 , Zhiping Li  1 , Yuli Wang  1 , Yang Yang  1 , Wei Gong  1 , Meiyan Yang  1 , Xiaolong Kong  2 , Chunsheng Gao  1
Affiliations

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

Yuanyuan Meng et al. Int J Pharm X. .

Abstract

Rivaroxaban (RIV) is a direct Factor Xa inhibitor anticoagulant, but the oral bioavailability of RIV is estimated to be only 60% due to its poor solubility. The aim of the present study was to improve the solubility and bioavailability of RIV. Five cocrystals-p-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DBA), nicotinamide (NA), isonicotinamide (IA), and succinic acid (SA)-were used as cofomers and were successfully obtained and characterized by powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectra. RIV-DBA and RIV-HBA cocrystals showed obvious improvements in solubility, dissolution (under sink conditions), and intrinsic dissolution rates versus RIV. Moreover, the dissolution of RIV-HBA, RIV-DBA, and RIV-SA cocrystals under non-sink conditions showed obvious "spring and parachute" patterns. The in vitro permeability levels in a Caco-2 cell model of RIV-DBA and RIV-IA cocrystals were significantly improved versus RIV. Pharmacokinetic studies in beagle dogs showed that RIV-DBA and RIV-HBA cocrystals had higher bioavailability than RIV. The enhancements in solubility and bioavailability indicate the potential of RIV cocrystals as a better candidate for the treatment of thrombosis versus RIV.

Keywords: Beagle dogs; Cocrystals; Dissolution; Permeation; Pharmacokinetics; Rivaroxaban; Solubility.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Unlabelled Image
Graphical abstract
Fig. 1
Fig. 1
Molecular structure of rivaroxaban (RIV), 4-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid(DBA), nicotinamide (NA), Isonicotinamide (IA), and succinic acid(SA).
Fig. 2
Fig. 2
PXRD (a), DSC (b), and FTIR (c) patterns of RIV-HBA(1), RIV-DBA(2), RIV-NA(3), RIV-IA(4), and RIV-SA(5). RIV: black curve, coformers: blue curve, PM: green curve, cocrystals: red curve. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Solubility of RIV from single components. PMs (a) and its cocrystals (b) in water and SDS solutions at 0.2% and 0.4% (w/v) levels (n = 3). *P < 0.05, **P < 0.01, compared to RIV. (c) The pH values of the bulk media solutions after solubility testing (mean ± SD, n = 3).
Fig. 4
Fig. 4
Powder dissolution profiles of RIV(a), RIV-HBA (b), RIV-DBA (c), RIV-NA (d), RIV-IA (e), and RIV-SA (f) in water and SDS solutions at 0.2% and 0.4% (w/v) levels under sink conditions (mean ± SD, n = 3).
Fig. 5
Fig. 5
Powder dissolution profiles of RIV, RIV-HBA, RIV-DBA, RIV-NA, RIV-IA, and RIV-SA cocrystals in water under non-sink conditions (mean ± SD, n = 3).
Fig. 6
Fig. 6
Intrinsic dissolution curves of RIV-DBA(a) and RIV-HBA(b) in pH 1.2 buffer at 37 °C (mean ± SD, n = 3).
Fig. 7
Fig. 7
(a) Results of cell cytotoxicity (n = 6). (b) Apparent permeability coefficients (Papp) of RIV, PMs, and its cocrystals across Caco-2 monolayer (n = 6). *P < 0.05 or **P < 0.01 compared to RIV. All the data are reported as the mean ± SD of three independent experiments.
Fig. 8
Fig. 8
Plasma concentration vs time profiles of RIV after oral administration to dogs of RIV, RIV-HBA cocrystal, RIV/HBA PM, RIV-DBA cocrystal, or RIV-DBA PMs (mean ± SD, n = 6).
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