Inhalable Nanocrystal-in-Microparticle of Linezolid in Pulmonary Tuberculosis

Tuberculosis (TB) remains a major global health challenge, necessitating the development of advanced pulmonary drug delivery systems to improve therapeutic efficacy. Linezolid (LZD), a second-line oxazolidinone antibiotic, is effective against multidrug-resistant Mycobacterium tuberculosis but is associated with systemic adverse effects when administered orally for prolonged periods.

This study aimed to engineer and optimise LZD nanocrystals (LZD-NCs) in microparticles for dry powder inhalation (DPI) using a Quality by Design (QbD)-based Central Composite Design (CCD) approach to enhance localised pulmonary delivery.

LZD-NCs were initially prepared by high-pressure homogenization (HPH) and subsequently converted into respirable nanocrystals in microparticles (LZD-NIM) using spray drying. The LZD-NCs formulation was optimised using CCD. The developed formulation was evaluated for physicochemical characteristics, including solid-state characterisation, in vitro drug-release study, kinetic study, and aerosolisation behaviour and stability.

The optimised formulation exhibited an average particle size of 239.5 ± 16.30 nm, polydispersity index (PDI) of 0.285 ± 0.042, and surface charge of -34.5 ± 1.84 mV, indicating acceptable colloidal stability. Later, NIM effectively retained the physicochemical integrity of LZD-NCs. The developed NIM formulation exhibited improved drug release of 61.39% over 24 h, compared with pure LZD at 37.26%. An in vitro aerosolisation study demonstrated appropriateness for deep lung deposition of NIM with a mass median aerodynamic diameter (MMAD) of 2.9 ± 0.15 µm and high fine particle fractions (FPF) of 76.12 ± 1.3%.

The engineered LZD-NIM successfully yielded a highly stable, aerodynamically efficient DPI platform with sustained drug release kinetics. The engineered platform demonstrates its potential as an effective pulmonary drug-delivery system for TB treatment.