Pulmonary drug delivery: physiologic and mechanistic aspects.

Peptide and protein drugs are being used increasingly in major research and development programs in the pharmaceutical industry and are also an important class of therapeutic agents due to advances in genetic engineering and biotechnology. Systemic delivery of these macromolecular drugs, however, has been limited to the parenteral route largely because of their extensive presystemic elimination when taken orally. Faced with this dilemma concerning the systemic delivery of these macromolecules with their unique conformational complexity for therapeutic activity, pharmaceutical scientists have evaluated the potential of various non-oral routes of administration as alternatives. Despite the tremendous efforts that have been devoted to this problem, only limited success has been achieved--mostly with small peptides. Growing attention has been given to the potential of a pulmonary route as an alternative non-invasive means for systemic delivery of peptide/protein-based therapeutic agents due to the fact that the lung provides a huge but extremely thin absorptive mucosal membrane. Although current studies show great promise, pulmonary delivery of therapeutic peptides and proteins is complicated by the complexity of the anatomic structure of the human respiratory system and the influence on drug deposition exerted by respiration. This review discusses the fundamental structure and physiology of the human respiratory system, current methodology used to study pulmonary drug absorption, approaches of drug delivery to the distal lung, and recent progress in pulmonary drug delivery by case studies. The mechanisms of pulmonary drug absorption are also discussed.