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<p>Ticagrelor (TC), a reversible P2Y12 receptor antagonist, is widely used for managing acute coronary syndromes but suffers from low aqueous solubility (10&#xa0;µg/mL) and poor oral bioavailability (36%), limiting its clinical utility. This study aimed to develop an intelligent delivery system using D-α-tocopheryl polyethylene glycol succinate (TPGS)–based polymeric micelles (PMs) to enhance TC solubility, stability, and antiplatelet efficacy. Through molecular docking and molecular dynamics simulation, TPGS demonstrated the most favourable interaction with TC (binding energy: − 4.2&#xa0;kcal/mol), which was further supported by density functional theory analysis (HOMO–LUMO gap: 4.49&#xa0;eV). TC-loaded micelles (TC-TPGS5-PMs) were prepared using a direct dissolution method and exhibited a mean particle size of 9.1 ± 0.06&#xa0;nm, PDI 0.134 ± 0.01, and a 51-fold solubility enhancement compared to free TC. Structural characterization (DSC, PXRD, FTIR) confirmed amorphous drug encapsulation without chemical interaction, and cryo-HR-TEM revealed spherical morphology. In vitro studies showed sustained drug release over 12&#xa0;h and &gt; 95% cell viability in Caco-2 cells. In vivo pharmacodynamic evaluation demonstrated significantly prolonged bleeding time, indicating enhanced antiplatelet activity compared to marketed TC tablets. These findings establish TPGS-based micelles as a promising oral nanocarrier platform for improving TC’s bioavailability, therapeutic performance, and potential for dose optimization in clinical settings.</p> Graphical Abstract <p></p>

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In Silico Guided Design of TPGS-Derived Polymeric Micelles for Improved Solubility and Antiplatelet Efficacy of Ticagrelor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月20日

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  • Riddhi Gandhi,
  • Arzoo Sekhani,
  • Bhavin Vyas,
  • Heena Parmar,
  • Bhaveshkumar Makwana,
  • Sonal Thakore,
  • Nimeet Desai,
  • Lalitkumar K. Vora,
  • Pranav Shah

摘要

Ticagrelor (TC), a reversible P2Y12 receptor antagonist, is widely used for managing acute coronary syndromes but suffers from low aqueous solubility (10 µg/mL) and poor oral bioavailability (36%), limiting its clinical utility. This study aimed to develop an intelligent delivery system using D-α-tocopheryl polyethylene glycol succinate (TPGS)–based polymeric micelles (PMs) to enhance TC solubility, stability, and antiplatelet efficacy. Through molecular docking and molecular dynamics simulation, TPGS demonstrated the most favourable interaction with TC (binding energy: − 4.2 kcal/mol), which was further supported by density functional theory analysis (HOMO–LUMO gap: 4.49 eV). TC-loaded micelles (TC-TPGS5-PMs) were prepared using a direct dissolution method and exhibited a mean particle size of 9.1 ± 0.06 nm, PDI 0.134 ± 0.01, and a 51-fold solubility enhancement compared to free TC. Structural characterization (DSC, PXRD, FTIR) confirmed amorphous drug encapsulation without chemical interaction, and cryo-HR-TEM revealed spherical morphology. In vitro studies showed sustained drug release over 12 h and > 95% cell viability in Caco-2 cells. In vivo pharmacodynamic evaluation demonstrated significantly prolonged bleeding time, indicating enhanced antiplatelet activity compared to marketed TC tablets. These findings establish TPGS-based micelles as a promising oral nanocarrier platform for improving TC’s bioavailability, therapeutic performance, and potential for dose optimization in clinical settings.

Graphical Abstract