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Nowadays, the resistance of bacterial biofilms towards the available antibiotics is a severe problem. Therefore, many efforts were devoted to develop new formulations using nanotechnology. We have developed an inhalable microparticle formulation using spray-drying combining multiple drugs: an antibiotic (tobramycin, ciprofloxacin or azithromycin), N-acetylcysteine (NAC), and curcumin (Cur). The use of PLGA nanoparticles (NP) also allowed incorporating curcumin to facilitate spray drying and modify the release of some compounds. The aerosolizable microparticles formulations were characterized in terms of size, morphology, and aerodynamic properties. Biocompatibility when tested on macrophage-like cells was acceptable after 20 h exposure for concentrations up to at least 32 µg/mL. Antibacterial activity of free drugs versus drugs in the multiple drug formulations was evaluated on P. aeruginosa in the same range. When co-delivered the efficacy of tobramycin was enhanced compared to the free drug for the 1 µg/mL concentration. The combinations of azithromycin and ciprofloxacin with NAC and Cur did not show an improved antibacterial activity. Bacteria-triggered cytokine release was not inhibited by free antibiotics, except for TNF-α. In contrast, the application of NAC and the addition of curcumin-loaded PLGA NPs showed a higher potential to inhibit TNF-α, IL-8, and IL-1β release. Overall, the approach described here allows simultaneous delivery of antibacterial, mucolytic, and anti-inflammatory compounds in a single inhalable formulation and may therefore pave the way for a more efficient therapy of pulmonary infections., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The majority of the currently used and developed anti-infectives are poorly water-soluble molecules. The poor solubility might lead to limited bioavailability and pharmacological action of the drug. Novel pharmaceutical materials have thus been designed to solve those problems and improve drug delivery. In this study, we propose a facile method to produce submicrocarriers (sMCs) by electrostatic gelation of anionic ß-cyclodextrin (aß-CD) and chitosan. The average hydrodynamic size ranged from 400 to 900 nm by carefully adjusting polymer concentrations and N/C ratio. The distinct host-guest reaction of cyclodextrin derivative is considered as a good approach to enhance solubility, and prevent drug recrystallization, and thus was used to develop sMC to improve the controlled release profile of a poorly soluble and clinically relevant anti-infective ciprofloxacin. The optimal molar ratio of ciprofloxacin to aß-CD was found to be 1:1, which helped maximize encapsulation efficiency (∼90%) and loading capacity (∼9%) of ciprofloxacin loaded sMCs. Furthermore, to recommend the future application of the developed sMCs, the dependence of cell uptake on sMCs size (500, 700, and 900 nm) was investigated in vitro on dTHP-1 by both flow cytometry and confocal microscopy. The results demonstrate that, regardless of their size, an only comparatively small fraction of the sMCs were taken up by the macrophage-like cells, while most of the carriers were merely adsorbed to the cell surface after 2 h incubation. After continuing the incubation to reach 24 h, the majority of the sMCs were found intracellularly. However, the sMCs had been designed to release sufficient amount of drug within 24 h, and the subsequent phagocytosis of the carrier may be considered as an efficient pathway for its safe degradation and elimination. In summary, the developed sMC is a suitable system with promising perspectives recommended for pulmonary extracellular infection therapeutics.

Purpose: The aim of this work was to develop clarithromycin microparticles (CLARI-MP) and evaluate their aerodynamic behavior, safety in bronchial cells and anti-bacterial efficacy., Methods: Microparticles containing clarithromycin were prepared as dry powder carrier for inhalation, using leucine and chitosan. CLARI-MP were deposited on Calu-3 grown at air-interface condition, using the pharmaceutical aerosol deposition device on cell cultures (PADDOCC). Deposition efficacy, transport across the cells and cytotoxicity were determined. Anti-antibacterial effect was evaluated against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus., Results: Microparticles were of spherical shape, smooth surface and size of about 765 nm. Aerosolization performance showed a fine particle fraction (FPF) of 73.3%, and a mass median aerodynamic diameter (MMAD) of 1.8 μm. Deposition on Calu-3 cells using the PADDOCC showed that 8.7 μg/cm(2) of deposited powder were transported to the basolateral compartment after 24 h. The safety of this formulation is supported by the integrity of the cellular epithelial barrier and absence of toxicity, and the antimicrobial activity demonstrated for Gram positive and Gram negative bacteria., Conclusions: The appropriate aerodynamic properties and the excellent deposition on Calu-3 cells indicate that clarithromycin microparticles are suitable for administration via pulmonary route and are efficient to inhibit bacteria proliferation.