Stabilization of aerosolizable nano-carriers by freeze-drying.

PURPOSE: This study investigates the feasibility of freeze-drying aerosolizable nano-carriers (NC) by the use of different lyoprotective agents (LPA) and the influence of the freeze-drying on the physicochemical properties of these nano-carriers and on their aerosolization. METHODS: Nano-carriers were prepared from fast-degrading polymers, DMAPA(24)-PVAL-g-PLGA(1:7.5) and DEAPA(26)-PVAL-g-PLGA(1:10), and freeze-dried using increasing concentrations of different LPA. The hydrodynamic diameter, zeta potential and morphology (atomic force microscopy) of NC were characterized before and after freeze-drying. The ability to aerosolize using a jet nebulizer and an electronic micro-pump nebulizer was also investigated. RESULTS: Freeze-drying with LPA led to a decreased zeta-potential of NC and changes in size about 20 nm without alteration in shape, whereas lyophilizates without LPA were found to aggregate. While freeze-drying was positively affected by increasing concentrations, it was not influenced by the type of LPA. The possibility for aerosolization was not influenced by any LPA. CONCLUSIONS: Freeze-drying with LPA is a suitable method to physically stabilize fast-degrading NC from aqueous suspensions without influencing the aerosolizability.

Pulmonary drug delivery with aerosolizable nanoparticles in an ex vivo lung model.

The use of colloidal carrier systems for pulmonary drug delivery is an emerging field of interest in nanomedicine. The objective of this study was to compare the pulmonary absorption and distribution characteristics of the hydrophilic model drug 5(6)-carboxyfluorescein (CF) after aerosolization as solution or entrapped into nanoparticles in an isolated rabbit lung model (IPL). CF-nanoparticles were prepared from a new class of biocompatible, fast degrading, branched polyesters by a modified solvent displacement method. Physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, stability of nanoparticles to nebulization, aerosol characteristics as well as pulmonary dye absorption and distribution profiles after nebulization in an IPL were investigated. CF-nanoparticles were spherical in shape with a mean particle size of 195.3+/-7.1nm, a polydispersity index of 0.225+/-0.017 and a zeta-potential of -28.3+/-0.3mV. Encapsulation efficiencies of CF were as high as about 60% (drug loading of 3% (w/w)); 90% of the entrapped CF were released during the first 50min in vitro. Nanoparticle characteristics were not significantly affected by the aerosolization process utilizing a vibrating mesh nebulizer. After deposition of equal amounts of CF in the IPL, less CF was detected in the perfusate for CF-nanoparticles (plateau concentration 9.2+/-2.4ng/ml) when compared to CF aerosolized from solution (17.7+/-0.8ng/ml). In conclusion, the data suggest that inhalative delivery of biodegradable nanoparticles may be a viable approach for pulmonary drug delivery. Moreover, a targeting effect to the lung tissue is claimed.

Pulmonary absorption of aerosolized fluorescent markers in the isolated rabbit lung.

For the development of aerosolized controlled release formulations such as liposomes or nanoparticles, the use of suitable model drugs is necessary. This study compared the pulmonary absorption of the three structurally diverse fluorescent markers 5(6)-carboxyfluorescein (CF), 8-methoxypyrene-1,3,6-trisulfonic acid trisodium salt (MPTS) and rhodamine 6G (R6G) after nebulization in an isolated, perfused and ventilated rabbit lung. Aerosol particle size and lung deposition as well as lipophilicity of the fluorescent markers were determined. Dye concentrations were measured in the recirculating buffer and in the bronchoalveolar lavage. The MMAD of the dye aerosols ranged between 4.70 and 4.88 microm, total lung deposition was 0.40+/-0.05 ml. The 1-octanol/water partition coefficient as measure for lipophilicity was -3.45+/-0.16 for CF, -4.95+/-0.21 for MPTS and 2.69+/-0.18 for R6G. The perfusate concentration showed an increase to approximately 400 ng/ml (53.4+/-6.8% of the intrapulmonary deposited dye) for CF and approximately 230 ng/ml (29.1+/-2.0%) for MPTS, respectively; R6G concentration increased in the first 30 min to approximately 38 ng/ml followed by a gradual decrease to approximately 26 ng/ml (3.3+/-0.7%). In conclusion, these data suggest that the hydrophilic dye CF is suitable to study drug transport from aerosolized controlled release formulations across the lung barrier. In contrast, the highly water-soluble fluorescent probe MPTS demonstrates insufficient recovery and the lipophilic R6G high accumulation in lung tissue.