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<p>Ezetimibe (EZT), a BCS class II drug, is a selective cholesterol absorption inhibitor used to treat high blood cholesterol. However, its clinical efficacy is limited by poor solubility and bioavailability. This study aims to address the low solubility and bioavailability of EZT. Aiming to improve the solubility, dissolution, and bioavailability of this hydrophobic drug by formulating EZT nanocrystals (EZT-NCs) using an innovative antisolvent precipitation-ultrasonication method. This bottom-up approach of optimizing structure and properties through particle size reduction, followed by lyophilisation, holds promise for enhanced therapeutic performance and effectiveness. Optimization of variables, including solvent: antisolvent ratio, poloxamer188 (P188) concentration, and ultrasonication amplitude, was achieved using Box-Behnken Design (BBD) as a computational tool, to produce uniform nanosized crystals with good dispersibility. Optimized EZT-NCs showed a particle size of 340 ± 12.00&#xa0;nm, PDI of 0.12 ± 0.05, and zeta potential of -46 ± 0.15 mV. DSC and pXRD confirmed reduced crystallinity. Scanning Electron microscopy (SEM) confirmed a nanometric size range, and in vitro dissolution revealed 85.17% release for EZT-NCs within 1&#xa0;h, a 1.87-fold increase over pure EZT. The everted gut sac model showed EZT-NCs had 5.23 times higher permeability than pure EZT, due to their nanometric size and P-gp inhibition by P188. Furthermore, EZT-NCs achieved a Cmax of 8.22&#xa0;µg/mL, with an AUC <sub>0−48</sub> that was 2.15 times higher than pure EZT. EZT-NCs demonstrated improved aqueous solubility, dissolution range, and bioavailability, suggesting their potential for an enhanced oral delivery approach.</p>

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Structure-property Optimization of Ezetimibe Nanocrystals by Computationally Guided Bottom-up Engineering for Enhanced Bioavailability

  • 期刊论文

  • 发表日期：

    2026年1月16日

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  • Pratiksha R. Pathade,
  • Shubhangi A. Thool,
  • Varsha B. Pokharkar

摘要

Ezetimibe (EZT), a BCS class II drug, is a selective cholesterol absorption inhibitor used to treat high blood cholesterol. However, its clinical efficacy is limited by poor solubility and bioavailability. This study aims to address the low solubility and bioavailability of EZT. Aiming to improve the solubility, dissolution, and bioavailability of this hydrophobic drug by formulating EZT nanocrystals (EZT-NCs) using an innovative antisolvent precipitation-ultrasonication method. This bottom-up approach of optimizing structure and properties through particle size reduction, followed by lyophilisation, holds promise for enhanced therapeutic performance and effectiveness. Optimization of variables, including solvent: antisolvent ratio, poloxamer188 (P188) concentration, and ultrasonication amplitude, was achieved using Box-Behnken Design (BBD) as a computational tool, to produce uniform nanosized crystals with good dispersibility. Optimized EZT-NCs showed a particle size of 340 ± 12.00 nm, PDI of 0.12 ± 0.05, and zeta potential of -46 ± 0.15 mV. DSC and pXRD confirmed reduced crystallinity. Scanning Electron microscopy (SEM) confirmed a nanometric size range, and in vitro dissolution revealed 85.17% release for EZT-NCs within 1 h, a 1.87-fold increase over pure EZT. The everted gut sac model showed EZT-NCs had 5.23 times higher permeability than pure EZT, due to their nanometric size and P-gp inhibition by P188. Furthermore, EZT-NCs achieved a Cmax of 8.22 µg/mL, with an AUC 0−48 that was 2.15 times higher than pure EZT. EZT-NCs demonstrated improved aqueous solubility, dissolution range, and bioavailability, suggesting their potential for an enhanced oral delivery approach.