Remarkably, with the exception of anaesthetic gases, the ancient human practice of inhaling substances into the lungs for systemic effect has only just begun to be adopted by modern medicine. Treatment of asthma by inhaled drugs began in earnest in the 1950s, and now such 'topical' or targeted treatment with inhaled drugs is considered for treating many other lung diseases. More recently, major advances have led to increasing interest in systemic delivery of drugs by inhalation. Small molecules can be delivered with very rapid action, low metabolism and high bioavailability; and macromolecules can be delivered without injections, as highlighted by the recent approval of the first inhaled insulin product. Here, we review these advances, and discuss aspects of lung physiology and formulation composition that influence the systemic delivery of inhaled therapeutics.

No abstract

The lung is naturally permeable to all small-molecule drugs studied and to many therapeutic peptides and proteins. Absorption can be estimated using a simple animal test, intratracheal instillation. Inhalation offers a noninvasive route for the delivery of peptides and proteins that otherwise must be injected. Peptides that have been chemically altered to inhibit peptidase enzymes exhibit very high bioavailabilities by the pulmonary route. Natural mammalian peptides, less than about 30 amino acids, are broken down in the lung by ubiquitous peptidases and have very poor bioavailabilities. In general, proteins with molecular weights between 6,000 and 50,000 D are relatively resistant to most peptidases and have good bioavailabilities following inhalation. For larger proteins the bioavailability picture is not clear. Although the lung is rich in antiproteases, aggregation of inhaled proteins will stimulate opsonization (coating) by special proteins in the lung lining fluids, which will then mark the aggregated proteins for phagocytosis and intracellular enzymatic destruction. Small peptides and proteins are absorbed more rapidly after inhalation than after subcutaneous injection. For other small molecules, inhalation is also a fast way to get into the body because drug efflux transporters and metabolizing enzymes are present in the lung at much lower levels than the gastrointestinal tract. Lipophilic small molecules are absorbed extremely fast, t(1/2) (abs) approximately 1 to 2 minutes. Water-soluble small molecules are absorbed rapidly t(1/2) (abs) approximately 65 minutes. Small molecules can exhibit prolonged absorption if they are highly insoluble or highly cationic. Encapsulation in slow release particles such as liposomes can also be used to control absorption.

No abstract

No abstract