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Objective <p>This study explores the co-spray-drying of chitosan and L-leucine to optimize inhalable microparticles for heparin sodium. Chitosan provides sustained release and pulmonary retention, while L-leucine improves powder dispersibility and aerosolization performance. By tuning the chitosan-to-leucine ratio, the formulation achieves an optimal balance between deep lung deposition and prolonged therapeutic effect, offering a promising strategy for polysaccharide-based pulmonary delivery.</p> Methods <p>Inhalable microparticles were prepared via co-spray-drying of heparin sodium with chitosan and L-leucine. <i>In-vitro</i> aerosolization performance was evaluated using the Next Generation Impactor. Particle morphology was examined via scanning electron microscopy (SEM). Solid-state properties were analyzed using X-ray powder diffraction (XRPD) to assess changes in crystallinity. Stability was assessed at 25&#xa0;°C and 55% RH over 4&#xa0;weeks. Drug release was studied using the <i>in-vitro</i> dialysis method and modeled with five kinetic models: Zero-order, First-order, Higuchi, Hixson–Crowell, and Korsmeyer–Peppas.</p> Results <p>Heparin sodium microparticles containing chitosan and L-leucine exhibited favorable aerosolization performance, especially in the HSCL1 formulation. SEM showed that L-leucine-induced wrinkling improved dispersibility, while excess chitosan caused surface cracking. XRPD analysis indicated that chitosan suppressed crystallinity while L-leucine retained partial crystalline features, supporting matrix stability and powder dispersion. <i>In-vitro</i> release study demonstrated biphasic kinetics in chitosan-containing formulations. HSCL1 showed sustained, non-Fickian release and enhanced storage stability.</p> Conclusion <p>Co-spray-dried heparin sodium microparticles with chitosan and L-leucine achieved balanced aerosolization performance, sustained release, and storage stability. Their combination overcomes the limitations of single-excipient systems. The optimized formulation demonstrates strong potential for effective pulmonary drug delivery with improved therapeutic consistency.</p> Graphical Abstract <p></p>

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Evaluation of the Combination of L‑leucine to Chitosan on Sustained Release of Inhalable Heparin Sodium Microparticles

  • 期刊论文

  • 发表日期：

    2025年7月1日

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  • Zhewei Liu,
  • Ying Ma,
  • Yuanyuan Shao,
  • Xiaoyang Wei,
  • Binjie Hu,
  • Jesse Zhu

摘要

Objective

This study explores the co-spray-drying of chitosan and L-leucine to optimize inhalable microparticles for heparin sodium. Chitosan provides sustained release and pulmonary retention, while L-leucine improves powder dispersibility and aerosolization performance. By tuning the chitosan-to-leucine ratio, the formulation achieves an optimal balance between deep lung deposition and prolonged therapeutic effect, offering a promising strategy for polysaccharide-based pulmonary delivery.

Methods

Inhalable microparticles were prepared via co-spray-drying of heparin sodium with chitosan and L-leucine. In-vitro aerosolization performance was evaluated using the Next Generation Impactor. Particle morphology was examined via scanning electron microscopy (SEM). Solid-state properties were analyzed using X-ray powder diffraction (XRPD) to assess changes in crystallinity. Stability was assessed at 25 °C and 55% RH over 4 weeks. Drug release was studied using the in-vitro dialysis method and modeled with five kinetic models: Zero-order, First-order, Higuchi, Hixson–Crowell, and Korsmeyer–Peppas.

Results

Heparin sodium microparticles containing chitosan and L-leucine exhibited favorable aerosolization performance, especially in the HSCL1 formulation. SEM showed that L-leucine-induced wrinkling improved dispersibility, while excess chitosan caused surface cracking. XRPD analysis indicated that chitosan suppressed crystallinity while L-leucine retained partial crystalline features, supporting matrix stability and powder dispersion. In-vitro release study demonstrated biphasic kinetics in chitosan-containing formulations. HSCL1 showed sustained, non-Fickian release and enhanced storage stability.

Conclusion

Co-spray-dried heparin sodium microparticles with chitosan and L-leucine achieved balanced aerosolization performance, sustained release, and storage stability. Their combination overcomes the limitations of single-excipient systems. The optimized formulation demonstrates strong potential for effective pulmonary drug delivery with improved therapeutic consistency.

Graphical Abstract