In immunologic lung disorders such as sarcoid activated alveolar macrophages are key to the pathophysiology of the alveolitis. These disorders can be successfully treated with systemic corticoids. Since therapy is often compromised by toxic side effects, localized inhalation therapy would be optimal. However, due to the poor aqueous solubility of corticoids, no inhalable dosage form currently exists which is optimally suitable for small particle nebulization to alveolar lung regions, where the inflammation occurs. We propose a novel therapeutic approach to such immunologic lung disorders: Alveolar delivery of liposome-incorporated corticoids by aerosol in order to promote corticoid uptake by alveolar macrophages, and thus modulate the inflammatory alveolitis at the macrophage level. The overall objective of this project is to initiate research that will lead to improved inhalation therapy of immunologic lung disorders, using sarcoid as an immunologically well-defined and corticoid- responsive example. The rationale is that corticoid inhalation could be more effective by targeting liposomal drug directly to alveolar lung regions and to macrophages. While optimal therapeutically effective levels could be established, systemic drug levels, thus side effects would be significantly reduced. Prolonged retention of liposome-corticoid in the lung may result in prolonged therapeutic efficacy at the cellular level. We propose to (1) design lyophilized liposome-corticoid dosage forms suitable for small particle aerosolization; (2) compare in vitro human macrophage uptake and receptor binding of liposome-corticoid and corticoid in solution; (3) determine the efficacy of liposome-corticoids on regulation of human macrophage immune functions n vitro; and (4) determine the in vivo distribution of liposome corticoids in rat lung, plasma and extrapulmonary tissues.
