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. 2025 Jul;42(7):1167-1180.
doi: 10.1007/s11095-025-03883-7. Epub 2025 Jul 1.

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

Zhewei Liu  1   2   3 , Ying Ma  2   4 , Yuanyuan Shao  3 , Xiaoyang Wei  3 , Binjie Hu  5 , Jesse Zhu  6   7   8
Affiliations

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

Zhewei Liu et al. Pharm Res. 2025 Jul.

Abstract

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.

Keywords: Chitosan; Dry powder inhalers; Inhalable heparin sodium; Pulmonary drug delivery; Sustained release.

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Conflict of interest statement

Declarations. Conflict of interest: 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.

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