The Particle has Landed—Characterizing the Fate of Inhaled Pharmaceuticals

Abstract

Although there is a modest body of literature on the absorption of inhaled pharmaceuticals by normal lungs and some limited information from diseased lungs, there is still a surprising lack of mechanistic knowledge about the details of the processes involved. Where are molecules absorbed, what mechanisms are involved, how well are different lung regions penetrated, what are the determinants of metabolism and dissolution, and how best can one retard the clearance of molecules deposited in the lung or induce intracellular uptake by lung cells? Some general principles are evident: (1) small hydrophobic molecules are absorbed very fast (within tens of seconds) usually with little metabolism; (2) small hydrophilic molecules are absorbed fast (within tens of minutes), again with minimal metabolism; (3) very low water solubility of the drug can retard absorption; (4) peptides are rapidly absorbed but are significantly metabolized unless chemically protected against peptidases; (5) larger proteins are more slowly absorbed with variable bioavailabilities; and 6) insulin seems to be best absorbed distally in the lungs while certain antibodies appear to be preferentially absorbed in the upper airways. For local lung disease applications, and some systemic applications as well, many small molecules are absorbed much too fast for convenient and effective therapies. For systemic delivery of peptides and proteins, absorption may sometimes be too fast. Bioavailabilities are often too low for cost-effective and reliable treatments. A better understanding of the determinants of pulmonary drug dissolution, absorption, metabolism, and how to target specific regions and/or cells in the lung will enable safer and more effective inhaled medicines in the future.

Dry powder inhalation: past, present and future

“…Inhalation seems attractive as noninvasive route for the delivery of peptides and proteins that otherwise must be injected, because the respiratory tract offers an enormous absorptive surface area for drug absorption [151,152]. It has long been believed that deposition in the most distal airways is needed for a high and reliable bioavailability.…”

“…However, it is now recognized that the preferred site of deposition may depend on the type of drug, e.g. certain antibodies are preferentially absorbed in the upper airways [152].…”

Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates

“…(11,12) It is expected that regional and local deposition patterns of drugs in the lungs will influence efficacy and treatment success. (13,14) Furthermore, efficacy also depends on drug dissolution, absorption, and clearance. (13) Departments of 1 Mechanical and Nuclear Engineering and 2 Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia.…”

“…(13,14) Furthermore, efficacy also depends on drug dissolution, absorption, and clearance. (13) Departments of 1 Mechanical and Nuclear Engineering and 2 Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia.…”

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

“…The Orlando meeting builds upon, among other things, the published outputs from the "Thousand Years of Pharmaceutical Aerosols" meeting in Iceland 5 years ago which considered the question "what remains to be done in the field of pharmaceutical aerosol science" (1). In vitro testing of OIP was reviewed in outputs from the meeting in Iceland (2,3). In this article, we consider subsequent developments and the extent to which research priorities are being addressed.…”