EFFECT OF DOSE AND RELEASE RATE ON PULMONARY TARGETING OF LIPOSOMAL TRIAMCINOLONE ACETONIDE PHOSPHATE

Purpose. To demonstrate the importance of dose and drug release rate f or pulmonary targeting of inhaled glucocorticoids using an animal mode l of intrapulmonary drug deposition. Methods. Liposomes composed of 1, 2-distearoyl phosphatidylcholine (DSPC), 1,2-distearoyl phosphatidylgl ycerol (DSPG) and triamcinolone acetonide phosphate (TAP) or liposomes containing triamcinolone acetonide CTA) were prepared by a mechanical dispersion method followed by extrusion through polycarbonate membran es. Encapsulation efficiency was assessed after size exclusion gel chr omatography by reverse phase HPLC. The effect of liposome size (200 nm and 800 nm) on the release kinetics of water-soluble encapsulated mat erial was determined in vitro at 37 degrees C using 6-carboxyfluoresce in as a marker and Triton X-100 (0.03%) as a leakage inducer. To inves tigate the relationship between drug release and pulmonary targeting, 100 mu g/kg of TAP in 800 nm liposomes was delivered to male rats by i ntratracheal instillation (IT) and the results compared to data for 10 0 mu g/kg TA liposomes (recently shown to exhibit a rapid drug release under sink conditions) and to previous studies reported for an equal dose of TAP in solution and TAP in 200 nm (1). Pulmonary targeting was assessed by simultaneously monitoring glucocorticoid receptor occupan cy over time in lung and liver using an ex vivo receptor binding assay as a pharmacodynamic measure of glucocorticoid action. To assess the effect of dose on pulmonary targeting experiments were performed using 2.5, 7.5, 25, 100, and 450 mu g/kg of TAP in 800 nm liposomes. Result s. The in vitro efflux of 6-carboxyfluorescein from (DSPC:DSPG) liposo mes after exposure to Triton-X was biexponential. The terminal half-li ves of 3.7 h and 9.0 h for the 200 nm and 800 nm liposomes, respective ly, demonstrated that larger liposomes promote slower release of encap sulated water-soluble solute while previous results already indicated that encapsulation of lipophilic TA does not result in sustained relea se. Pulmonary targeting, defined as the difference between cumulative lung and liver receptor occupancies was most pronounced for the 800 nm liposomes (370%h), followed by the 200 nm preparation (150%*h). No t argeting was observed for TAP in solution (30%h) or the rapid releasi ng TA liposome preparation. Correspondingly, the mean pulmonary effect time (MET) increased from 2.4-3.0 hr for TA liposomes or TAP in solut ion to 5.7 h and >6.2 h for TAP in 200 nm and in 800 nm liposomes, res pectively. Escalating doses of TAP encapsulated in 800 nm liposomes re vealed a distinct bell shaped relationship between the TAP dose and pu lmonary targeting with a maximum occurring at 100 mu g/kg (370%h). Co nclusions. The in vivo data presented here confirm that pulmonary resi dence time and dose affect the extent of lung targeting of glucocortic oids delivered via the lung.