Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis

J Control Release. 2024 May:369:231-250. doi: 10.1016/j.jconrel.2024.03.013. Epub 2024 Mar 29.


Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.e., dual micro-nano inhalation strategy). The spherical particles are synthesised through the condensation of nano-sized amorphous silicon dioxide resulting in high surface area, disordered mesoporous silica particles (MSPs) with monodispersed size of 2.43 μm. Clofazimine (CLZ), a drug shown to be effective against multidrug-resistant tuberculosis, was encapsulated in the MSPs obtaining a dry powder formulation with high respirable fraction (F.P.F. <5 μm of 50%) without the need of additional excipients. DSC, XRPD, and Nitrogen adsorption-desorption indicate that the drug was fully amorphous when confined in the nano-sized pores (9-10 nm) of the MSPs (shelf-life of 20 months at 4 °C). Once deposited in the lung, the CLZ-MSPs exhibited a dual action. Firstly, the nanoconfinement within the MSPs enabled a drastic dissolution enhancement of CLZ in simulated lung fluid (i.e., 16-fold higher than the free drug), increasing mycobacterial killing than CLZ alone (p = 0.0262) and reaching concentrations above the minimum bactericidal concentration (MBC) against biofilms of M. tuberculosis (i.e., targeting extracellular bacteria). The released CLZ permeated but was highly retained in a Calu-3 respiratory epithelium model, suggesting a high local drug concentration within the lung tissue minimizing risk for systemic side effects. Secondly, the micron-sized drug carriers spontaneously dissolve in simulated lung fluid into nano-sized drug carriers (shown by Nano-FTIR), delivering high CLZ cargo inside macrophages and drastically decreasing the mycobacterial burden inside macrophages (i.e., targeting intracellular bacteria). Safety studies showed neither measurable toxicity on macrophages nor Calu-3 cells, nor impaired epithelial integrity. The dissolved MSPs also did not show haemolytic effect on human erythrocytes. In a nutshell, this study presents a low-cost, stable and non-invasive dried powder formulation based on a dual micro-nano carrier to efficiently deliver drug to the lungs overcoming technological and practical challenges for global healthcare.

Keywords: Clofazimine; Disordered mesoporous silica particles; Dissolution enhancement; Dried powder formulation; Dual micro-nano carrier; Lung drug delivery; Soluble carrier.

MeSH terms

  • Administration, Inhalation
  • Animals
  • Antitubercular Agents* / administration & dosage
  • Antitubercular Agents* / chemistry
  • Antitubercular Agents* / pharmacokinetics
  • Antitubercular Agents* / pharmacology
  • Antitubercular Agents* / therapeutic use
  • Clofazimine* / administration & dosage
  • Clofazimine* / pharmacokinetics
  • Clofazimine* / therapeutic use
  • Drug Carriers* / chemistry
  • Drug Delivery Systems
  • Drug Liberation
  • Humans
  • Lung* / metabolism
  • Mice
  • Mycobacterium tuberculosis / drug effects
  • Nanoparticles* / administration & dosage
  • Nanoparticles* / chemistry
  • Particle Size
  • Porosity
  • Silicon Dioxide / administration & dosage
  • Silicon Dioxide / chemistry
  • Tuberculosis / drug therapy


  • Antitubercular Agents
  • Drug Carriers
  • Clofazimine
  • Silicon Dioxide