Engineering Alginate-Based Dry Powder Microparticles to a Size Suitable for the Direct Pulmonary Delivery of Antibiotics.

The inhaled route is regarded as one of the most promising strategies as a treatment against pulmonary infections. However, the delivery of drugs in a dry powder form remains challenging. In this work, we have used alginate to form microparticles containing an antibiotic model (colistin sulfate). The alginate microparticles were generated by atomization technique, and they were characterized by antimicrobial in vitro studies against Pseudomonas aeruginosa. Optimization of different parameters allowed us to obtain microparticles as a dry powder with a mean size (Feret diameter) of 4.45 ± 1.40 µm and drug loading of 8.5 ± 1.50%. The process developed was able to concentrate most of the colistin deposits on the surface of the microparticles, which could be observed by SEM and a Dual-Beam microscope. This produces a fast in vitro release of the drug, with a 100% release achieved in 4 h. Physicochemical characterization using the FTIR, EDX and PXRD techniques revealed information about the change that occurs from the amorphous to a crystalline form of colistin. Finally, the cytotoxicity of microparticles was tested using lung cell lines (A549 and Calu-3). Results of the study showed that alginate microparticles were able to inhibit bacterial growth while displaying non-toxicity toward lung cells.

Excipient-Free Inhalable Microparticles of Azithromycin Produced by Electrospray: A Novel Approach to Direct Pulmonary Delivery of Antibiotics.

Inhalation therapy offers several advantages in respiratory disease treatment. Azithromycin is a macrolide antibiotic with poor solubility and bioavailability but with a high potential to be used to fight lung infections. The main objective of this study was to generate a new inhalable dry powder azithromycin formulation. To this end, an electrospray was used, yielding a particle size around 2.5 µm, which is considered suitable to achieve total deposition in the respiratory system. The physicochemical properties and morphology of the obtained microparticles were analysed with a battery of characterization techniques. In vitro deposition assays were evaluated after aerosolization of the powder at constant flow rate (100 L/min) and the consideration of the simulation of two different realistic breathing profiles (healthy and chronic obstructive pulmonary disease (COPD) patients) into a next generation impactor (NGI). The formulation was effective in vitro against two types of bacteria, Staphylococcus aureus and Pseudomonas aeruginosa. Finally, the particles were biocompatible, as evidenced by tests on the alveolar cell line (A549) and bronchial cell line (Calu-3).

Tuning Alginate Microparticle Size via Atomization of Non-Newtonian Fluids.

A new approach based on the atomization of non-Newtonian fluids has been proposed to produce microparticles for a potential inhalation route. In particular, different solutions of alginate were atomized on baths of different crosslinkers, piperazine and barium chloride, obtaining microparticles around 5 and 40 microns, respectively. These results were explained as a consequence of the different viscoelastic properties, since oscillatory analysis indicated that the formed hydrogel beads with barium chloride had a higher storage modulus (1000 Pa) than the piperazine ones (20 Pa). Pressure ratio (polymer solution-air) was identified as a key factor, and it should be from 0.85 to 1.00 to ensure a successful atomization, obtaining the smallest particle size at intermediate pressures. Finally, a numerical study based on dimensionless numbers was performed to predict particle size depending on the conditions. These results highlight that it is possible to control the microparticles size by modifying either the viscoelasticity of the hydrogel or the experimental conditions of atomization. Some experimental conditions (using piperazine) reduce the particle size up to 5 microns and therefore allow their use by aerosol inhalation.

Dry powder formulation for pulmonary infections: Ciprofloxacin loaded in chitosan sub-micron particles generated by electrospray.

Electrospray was used as a one-step technique to generate inhalable ciprofloxacin-loaded chitosan sub-micron particles with potential use in the treatment of pulmonary infections. The effect of operating parameters was studied and the preparation method optimized. The final sizes of ciprofloxacin-loaded particles were 386.1 ± 248.5 nm and 501.1 ± 276.3 nm for high and low molecular weight chitosan, respectively. The high surface charge of the particles formed, around +45 mV, enhances their mucoadhesive properties. The particles were biocompatible with alveolar cell line (A549), and showed a high antimicrobial activity against two of the most common respiratory pathogens Staphylococcus aureus and Pseudomonas aeruginosa.