Sustained Release of Antifibrotic Nintedanib from Polymer Microparticles Reduces Dosing Frequency While Reducing Inflammation in Murine Idiopathic Pulmonary Fibrosis.

Abstract

Purpose: Idiopathic pulmonary fibrosis (IPF) is a life-threatening, progressive lung disease with limited therapeutic options, often resulting in poor patient outcomes. Current treatments, such as Nintedanib (NTB) and Pirfenidone (PFD), require frequent administration, leading to adverse effects and low patient adherence. The purpose of this study was to investigate a sustained-release drug delivery system utilizing microparticles (MPs) composed of insoluble beta-cyclodextrin (β-CD) polymers to enhance the bioavailability and extend the release of NTB and PFD.

Methods: A multidisciplinary approach, including in silico modeling, in vitro assays, and in vivo studies, was employed to assess the efficacy of β-CD-polymer MPs as drug carriers.

Results: Molecular docking simulations and surface plasmon resonance studies demonstrated a stronger binding affinity of NTB to β-CD-polymer MPs compared to PFD, suggesting an extended delivery profile for NTB over PFD. Pharmacokinetic analysis in healthy mice confirmed sustained-release profiles for both drugs, with NTB maintaining therapeutic plasma concentrations for over 70 h. In a bleomycin-induced IPF mouse model, NTB-loaded β-CD-polymer MPs significantly reduced pro-inflammatory markers and required fewer injections than the standard daily NTB regimen.

Conclusion: These findings indicate that β-CD-polymer MPs may serve as a promising platform for reducing dosing frequency of NTB and enhancing therapeutic outcomes in the treatment of IPF.