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

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.