Development and bioavailability modulation of once-daily controlled release apixaban tablets by utilizing functional pharmaceutical excipients

Abstract

The aim of this study was to develop a once-daily controlled-release (CR) apixaban (APX) formulation that enhances bioavailability through dual mechanisms of P-glycoprotein (P-gp) inhibition and sustained drug release using selected functional pharmaceutical excipients.

Based on the screening of pharmaceutical excipients with enhanced solubility and P-gp inhibitory properties for APX, CR formulations containing polyethylene oxide (PEO 1,000,000 and 300,000) and D-α-Tocopheryl polyethylene glycol succinate (TPGS) were designed to simultaneously modulate the solubility, release rate, and P-gp inhibition to enhance the bioavailability of APX. Dissolution profiles were evaluated under three pH conditions (pH 1.2, pH 6.8, and pH-shift). In vivo pharmacokinetics were assessed in rats (n = 6 per group) using mini-tablets and in beagle dogs (n = 6 per group) using full-size tablets.

Caco-2 bidirectional transport studies provided direct cellular evidence that TPGS significantly reduces P-gp-mediated efflux (efflux ratio reduced from 2.94 to 1.77, 40% reduction), while PEO demonstrated moderate inhibitory effects (efflux ratio reduced to 2.27, 23% reduction), confirming the mechanistic basis for P-gp inhibition. In a preliminary pharmacokinetic experiment in rats, the presence of polymers (PEO and hydroxypropyl methylcellulose) and TPGS in the minitablet was crucial for enhancing APX bioavailability via concurrent P-gp inhibition and controlled release of solubilized APX.

Furthermore, the PEO- and TPGS-based CR APX matrix tablet (REX-PT) demonstrated enhanced bioavailability in beagle dogs compared with that of the hydroxypropyl methylcellulose (K100 and 4000)-based CR APX matrix tablet (REX-H) and immediate-release commercial reference tablet (Eliquis®) without the addition of TPGS. Interestingly, REX-PT demonstrated systemically bioequivalent exposure that could allow substitution for twice-daily Eliquis®, enabling once-daily dosing convenience.

Consequently, the current once-daily CR APX tablet utilizing functional pharmaceutical excipients such as PEO and TPGS could provide a strategic approach for enhancing the low bioavailability and frequent dosing requirements of commercial APX products.

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Materials

APX (purity ≥99.5%) was provided by Morepen Laboratories Ltd. (Himachal Pradesh, India). PEO (1,000,000; 300,000, Polyox™), selected for its matrix-forming and P-gp inhibitory properties, was supplied by Colorcon Inc. (Harleysville, PA, USA). Polyethylene oxide (PEO), a high molecular weight member of the polyethylene glycol family, demonstrated concentration-dependent inhibition of P-glycoprotein efflux in Caco-2 monolayer studies. Vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000).

Jiseok Yoo, Daehyeon Kim, Eun Hye You, Seohyeon Park, Jun-Bom Park, Chulhun Park, Beom-Jin Lee,
Development and bioavailability modulation of once-daily controlled release apixaban tablets by utilizing functional pharmaceutical excipients, Journal of Drug Delivery Science and Technology, Volume 119, 2026,
108135, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108135.

See also the interesting video on Vitamin E TPGS below and read more here