CHARACTERIZATION AND ADMINISTRATION OF CYCLOSPORINE LIPOSOMES AS A SMALL-PARTICLE AEROSOL

Systemically administered CsA has not consistently suppressed the pulm onary immunoreactivity that leads to rejection in lung transplant pati ents. Pulmonary T cells from patients given CsA systemically still ret ain their immunoreactivity, which can be suppressed with added CsA. Di rect application of CsA by aerosol to the respiratory epithelium shoul d achieve high lung concentrations with minimum systemic effects. In t he present study, CsA was most efficiently incorporated into liposomes composed of egg yolk phosphatidylcholine at a molar ratio of CsA to e gg yolk phosphatidylcholine of 1:20. These CsA liposomes retained thei r biological activity and were as effective as free CsA in the suppres sion of anti-CD3-stimulated [H-3]thymidine incorporation by mouse sple en cells. The generation of a small-particle aerosol of CsA liposomes had no effect on this biological activity. CsA liposome aerosol partic les have a mass median aerodynamic diameter of 2 mum, which allows for distribution of drug throughout the respiratory tract. Quantitation o f CsA in the lungs and blood of mice exposed to CsA liposome aerosols for 4 days showed that as little as 15 min daily (0.11 mg/kg/day) was sufficient to achieve an estimated concentration of CsA in respiratory secretions of 6 mug/ml without detectable blood levels. Thus, CsA lip osomes can be produced and aerosolized that achieve pulmonary concentr ations with sufficient immunosuppressive activity to be effective in t he treatment of lung diseases.