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Objectives <p>Cilostazol is a BCS class-II antiplatelet drug with a wide range of therapeutic actions, including anti-inflammatory, antioxidant, and antiapoptotic properties. Oral administration is associated with poor water solubility, limited absorption, and low bioavailability, which can be overcome by pulmonary administration. Despite of advancements, delivering poorly water-soluble drugs to the lungs with improved solubility, bioavailability, and stability and achieving excellent aerosolization continue to be substantial challenges.</p> Methods <p>In this study, cilostazol was formulated as a dry powder inhaler using cyclodextrin metal–organic framework (CD-MOF), i.e., CLZ-CD-MOF by vapor diffusion method. Molecular docking and molecular dynamic simulation confirmed the formation of a cilostazol nanocluster with CD-MOF and its thermodynamic stability.</p> Results <p>The free-energy estimation, hydrogen bond analysis, and the presence of CTAB confirmed the thermodynamic stability of cilostazol-CD-MOF with delta G of − 6.4 ± 2&#xa0;kcal/mol. Compared with CLZ-I formulation, i.e., micronized cilostazol with a DPI InhaLac®500, the cubic-shaped CLZ-CD-MOFs showed excellent aerodynamic performance owing to porous structure and lower density. The solubility of cilostazol significantly increased over a period of 24&#xa0;h with the CLZ-CD-MOFs. The dissolution study showed that cilostazol was released more rapidly from CLZ-CD-MOFs than from the CLZ-I formulation, i.e., over 90% release within 15&#xa0;min. The entrapment efficiency of CLZ-CD-MOF was approximately 96.39%. The CLZ-CD-MOF-F3 showed an EC50 value of 32.70&#xa0;µg /ml in the A549 cell line, suggesting its potential in acute lung injury and pulmonary fibrosis.</p> Conclusion <p>Therefore, γ-CD-MOF could be a safe and effective approach for delivering cilostazol to the lungs via dry powder inhalation.</p> Graphical abstract <p></p>

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Molecular dynamics (MD) simulation-guided design and development of a cilostazol-CD-MOF inhaler and its in vitro evaluation in pulmonary fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • Pranaya Misar,
  • Kishor Otari

摘要

Objectives

Cilostazol is a BCS class-II antiplatelet drug with a wide range of therapeutic actions, including anti-inflammatory, antioxidant, and antiapoptotic properties. Oral administration is associated with poor water solubility, limited absorption, and low bioavailability, which can be overcome by pulmonary administration. Despite of advancements, delivering poorly water-soluble drugs to the lungs with improved solubility, bioavailability, and stability and achieving excellent aerosolization continue to be substantial challenges.

Methods

In this study, cilostazol was formulated as a dry powder inhaler using cyclodextrin metal–organic framework (CD-MOF), i.e., CLZ-CD-MOF by vapor diffusion method. Molecular docking and molecular dynamic simulation confirmed the formation of a cilostazol nanocluster with CD-MOF and its thermodynamic stability.

Results

The free-energy estimation, hydrogen bond analysis, and the presence of CTAB confirmed the thermodynamic stability of cilostazol-CD-MOF with delta G of − 6.4 ± 2 kcal/mol. Compared with CLZ-I formulation, i.e., micronized cilostazol with a DPI InhaLac®500, the cubic-shaped CLZ-CD-MOFs showed excellent aerodynamic performance owing to porous structure and lower density. The solubility of cilostazol significantly increased over a period of 24 h with the CLZ-CD-MOFs. The dissolution study showed that cilostazol was released more rapidly from CLZ-CD-MOFs than from the CLZ-I formulation, i.e., over 90% release within 15 min. The entrapment efficiency of CLZ-CD-MOF was approximately 96.39%. The CLZ-CD-MOF-F3 showed an EC50 value of 32.70 µg /ml in the A549 cell line, suggesting its potential in acute lung injury and pulmonary fibrosis.

Conclusion

Therefore, γ-CD-MOF could be a safe and effective approach for delivering cilostazol to the lungs via dry powder inhalation.

Graphical abstract