Carrier-free combination for dry powder inhalation of antibiotics in the treatment of lung infections in cystic fibrosis.

The aim of the study was to develop an efficient combination antibiotic formulation containing tobramycin and clarithromycin as a dry powder for inhalation. A carrier-free formulation of the two drugs was produced by spray-drying and characterised for its aerodynamic behaviour by impaction tests with an NGI and release profiles. The particle size distribution, morphological evaluation and crystallinity state were determined by laser diffraction, scanning electron microscopy and powder X-ray diffraction, respectively. Drug deposition profiles were similar for the two antibiotics, which has a synergistic effect, allowing them to reach the target simultaneously at the expected dose. The release profiles show that tobramycin and clarithromycin should probably dissolve without any difficulties in vivo in the lung as 95% of tobramycin and 57% of clarithromycin mass dissolved in 10min for the spray-dried formulation. The FPF increased from 35% and 31% for the physical blend for tobramycin and clarithromycin, respectively, to 65% and 63% for the spray-dried formulation. The spray-dried formulation shows particularly high deposition results, even at sub-optimal inspiratory flow rates, and therefore, represents an attractive alternative in the local treatment of lung infection such as in cystic fibrosis.

New co-spray-dried tobramycin nanoparticles-clarithromycin inhaled powder systems for lung infection therapy in cystic fibrosis patients.

The aim of the study was to produce easily dispersible and porous agglomerates of tobramycin nanoparticles surrounded by a matrix composed of amorphous clarithromycin. Nanoparticles of tobramycin with a median particle size of about 400 nm were produced by high-pressure homogenisation. The results from the spray-dried powders showed that the presence of these nanoparticles enhanced powder dispersion during inhalation. Moreover, local drug deposition profiles were similar for the two antibiotics, allowing them to reach the target simultaneously. The dissolution-release profiles showed that tobramycin and clarithromycin might dissolve without any difficulties in the lung. The fine particle fraction increased from 35% and 31% for the physical blend for tobramycin and clarithromycin, respectively, to 63% and 62% for the spray-dried formulation containing nanoparticles. These new formulations, showing high lung deposition properties, even at sub-optimal inspiratory flow rates, represent a great possibility for advancing pulmonary drug administration and local therapy of lung infections.

Pharmacoscintigraphic and pharmacokinetic evaluation of tobramycin DPI formulations in cystic fibrosis patients.

Tobramycin dry powder formulations were evaluated by gamma scintigraphy and pharmacokinetic methods. In an open single-dose, three-treatment, three-period, cross-over study, nine cystic fibrosis patients received both the two test products and the reference product Tobi (nebulizer solution) in order to assess lung deposition and systemic comparative bioavailability of the two investigational inhaled products versus the marketed inhaled comparator product. The percentage of dose (mean+/-SD) in the whole lung was 53.0+/-10.0% for the tobramycin Form 1, 34.1+/-12.4% for the tobramycin Form 2 and 7.6+/-2.7% for the comparator product Tobi. Lung deposition expressed as a percentage of the nominal dose was thus estimated to be 7.0 and 4.5 times higher for the Tobra Form 1 and Tobra Form 2 than for the Tobi, respectively. Furthermore, the systemic bioavailability (adjusted to correspond to the same drug dose as that of the comparator product deposited in the lung) was found to be 1.6 times higher for the comparator product Tobi than for the two DPI formulations. The principal advantages of the DPI formulations include reduced systemic availability and thus, side effects, and higher dose levels of the drug at the site of drug action.

Formulation and characterization of lipid-coated tobramycin particles for dry powder inhalation.

PURPOSE: This study was conducted to develop and evaluate the physicochemical and aerodynamic characteristics of lipid-coated dry powder formulations presenting particularly high lung deposition. METHODS: Lipid-coated particles were prepared by spray-drying suspensions with different concentrations of tobramycin and lipids. The solid-state properties of the formulations, including particle size and morphology, were assessed by scanning electron microscopy and laser diffraction. Aerosol performance was studied by dispersing the powders into a Multistage Liquid Impinger and determining drug deposition by high-performance liquid chromatography. RESULTS: Particle size distributions of the formulations were unimodal, narrow with more than 90% of the particles having a diameter of less than 2.8 microm. All powder formulations exhibited mass median diameters of less than 1.3 and 3.2 microm, as determined by two different laser diffraction methods, the Malvern's Mastersizer and Spraytec, respectively. The fine particle fraction varied within a range of 50.5 and 68.3%. CONCLUSIONS: Lipid coating of tobramycin formulations resulted in a reduced agglomeration tendency and in high fine particle fraction values, thus improving drug deposition. The very low excipients content (about 5% m/m) of these formulations offers the benefit of delivering particularly huge concentrations of antibiotic directly to the site of infection, while minimizing systemic exposure, and may provide a valuable alternative treatment of cystic fibrosis.