Production of an Aerosol of Cyclosporine as a Prelude to Clinical Studies

Abstract

It has been proposed that the local administration of cyclosporine by aerosolization may be of potential benefit to patients with lung allografts. As a prelude to clinical studies with this agent, we produced an aerosol containing cyclosporine and measured its aerodynamic characteristics under simulated clinical conditions. Cyclosporine (200mg) was dissolved in 95% ethanol and aerosolized using a commercially available jet nebulizer (AeroTech II). A piston ventilator was used to maintain a constant breathing pattern. The aerosol was sampled using a multi-stage cascade impactor and the cyclosporine on each stage was measured by HPLC. The cyclosporine aerosol was found to have an MMAD of 1.2 μm with a σg of 2.1. The study was repeated with the addition of two radioactive labels, unbound Technetium (99mTc) and 99mTc bound to human serum albumin (99mTc-HSA). The aerodynamic mass distribution of the cyclosporine was unchanged by the addition of either radiolabel. Measurement of cyclosporine activity and radioactivity on each stage of the cascade impactor revealed that the distribution of the drug and radiolabel were similar and that there was a 1:1 relationship between the percentage of drug and the percentage of radioactivity nebulized. We also measured, under standard, simulated clinical conditions, the cyclosporine output from the nebulizer (inhaled mass). With a tidal volume of 750 cc, frequency of 20 min−1, and duty cycle 0.5, the inhaled mass equaled 24% of the original amount of drug placed in the nebulizer. We conclude that it is possible to produce an aerosolized form of cyclosporine, with aerodynamic characteristics unaffected by the radiolabel, likely to optimize peripheral airway/alveolar deposition.