The lung is the only organ in the body that receives entire cardiac output. There are 200–600 million alveoli in a normal human lung, which provide a large mucosal surface (~100 m2). These alveoli are highly permeable and have low enzymatic/metabolic activity, making them an attractive target for pulmonary drug delivery for systemic absorption. Pulmonary route of drug delivery also obviates hepatic first pass metabolism that could be a significant liability for certain orally delivered drugs. In addition, localized drug delivery for the treatment of lung disorders minimizes systemic side effects and metabolism, while allowing high local concentration, faster onset of action, and higher efficacy. An increasing number of drugs are being administered by the pulmonary route, including bronchodilators, corticosteroids, antibiotics, antifungal agents, antiviral agents, vasoactive drugs, DNase alpha (Pulmozyme, Genentech), and human insulin.
The lung has evolved to maintain sterility of its pathways and to avoid undesired airborne pathogens and particles through mechanisms such as (a) airway geometry, (b) localized high humidity, (c) mucociliary clearance, and (d) the presence of alveolar macrophages. When designing pulmonary drug delivery systems, you have to take many elements into consideration, such as size and drug loading of the particles, density of the particles, particle shape, etc. Ultimately, devices play a major role in the efficiency of pulmonary drug delivery by producing a respirable aerosol—a colloidal dispersion of a liquid or a solid in a gas—by actuation of a pressurized container or breath actuation.
Successful inhalation drug delivery requires close collaboration and coordination of interdependencies among drug substance, analytical, formulation, device, and target patient population characteristics to address the unique challenges and stringent requirements for the drug product. For example, air jet milling has typically been used to obtain particles of small molecule drugs in the desired size range for dry powder inhalers. The intensity of milling, the physical instability consequences of high surface energy of milled drug particles, and the time dependence or relaxation time for stabilization of surface properties after milling are important to reproducible drug product performance. Pulmonary delivery of protein and peptide drugs typically utilizes aqueous solutions of these drugs and faces unique physical (predominantly aggregation) and chemical (such as oxidation) challenges due to the complex secondary and tertiary structure of these macromolecules that makes them sensitive to fluid effects such as shear and viscosity.
The success of pulmonary drug delivery critically depends on the cross-functional collaborations that allow reproducibly delivering the right dose to the desired regions of the lung.
Get more in-depth with this topic by reading the January AAPS Newsmagazine cover story Biopharmaceutics of Inhalation Drug Delivery: At the Interface of Drug, Device, Formulation, and Patient Characteristics, and share your thoughts on the article in the comments section below.