Experimental pulmonary delivery of cyclosporin A by liposome aerosol

The utilization of CsA–liposome for aerosol delivery by jet nebulizers has potential advantages for clinical development including: aqueous compatibility, sustained pulmonary release to maintain therapeutic drug levels and facilitated delivery to alveolar macrophages and pulmonary lymphocytes. Inhalation of cyclosporin A (CsA)–dilauroylphosphatidylcholine (DLPC) liposome aerosols will theoretically result in localized and sustained delivery of therapeutic CsA concentrations within the lung as an alternative to local immunotherapy for pulmonary diseases. In the lung, targeted delivery of therapeutic CsA concentrations would require lower dosages than via conventional intravenous or oral routes of administration. Potential benefits from targeted lung delivery could include reduced systemic toxicity and prolonged immunosuppressive activity. Aerosol delivery systems have been developed to deposit drugs directly onto pulmonary surfaces at the sites of disease within the lung. A novel HPLC method for tissue analysis of CsA–liposomes is developed and utilized with a solid-phase extraction method to measure CsA recovered from Balb/c mouse lung tissues. A concentrated formulation containing 5 mg CsA–37.5 mg DLPC/ml was nebulized with an Aerotech II nebulizer generating an aerosol particle size distribution (mass median aerodynamic diameter (MMAD)) of 1.7 μm and geometric standard deviation (GSD) of 2.0. After a 15-min aerosol exposure, little of no CsA was detected in the blood, liver, kidney or spleen. The lung contained the highest organ CsA levels with high immunosuppressive activity demonstrating effective pulmonary targeting of the CsA–DLPC liposome aerosol. The results of this system will be utilized as the experimental basis for future pharmacokinetic, toxicological, immunosuppression and other biological studies.