Getting Drugs Across Biological Barriers

Abstract

The delivery of drugs to a target site frequently involves crossing biological barriers. The degree and nature of the impediment to flux, as well as the potential approaches to overcoming it, depend on the tissue, the drug, and numerous other factors. Here an overview of approaches that have been taken to crossing biological barriers is presented, with special attention to transdermal drug delivery. Technology and knowledge pertaining to addressing these issues in a variety of organs could have a significant clinical impact.

Keywords: biological barriers; drug delivery; transdermal transport.

Figure 1

Summary of strategies to overcome biological barriers. CPEs: chemical permeation enhancers.

Figure 2

Drug transport across skin. (a) The stratum corneum (SC) is the outermost layer of skin and the major barrier to transport. Molecules can permeate via the intercellular, transcellular, and intracellular routes. The cell layers discussed in the text are in black. (b) Permeation across the SC is primarily limited by lipids (mortar), which fill the spaces between corneocytes (bricks). (c) Lipids filling the spaces between corneocytes are arranged in a bilayer structure, with hydrophobic tails on the inside and polar head groups on the outside. Lipids are mainly cholesterol (yellow), free fatty acids (blue), and ceramides (green). (c) is adapted with permission from^[314]. Copyright 2011 American Chemical Society.

Figure 3

Total number of US FDA-approved transdermal drug formulations over time. Data were obtained from the FDA Orange Book.^[34]

Figure 4

Drug loading of macromolecule-based chemical permeation enhancers. (A) hyaluronic acid-drug conjugate; (B) drug-encapsulating dendrimer; (C) cyclodextrin-drug complex. The red spheres represent the drugs.

Figure 5

Physical mechanisms to enhance transdermal drug delivery. Blue dots represent therapeutics; white circies under single/dual frequency ultrasound represent microbubbles.

Figure 6

Selected peptide sequences of the three categories of skin penetrating peptides: cell-penetrating peptides, antimicrobial peptides, and phage peptides.

Figure 7

Schematic representation of an in-situ forming antibiotic-loaded hydrogel at the tympanic membrane (TM). Antibiotics diffuse out of the gel, across the TM (with the assistance of CPEs), and into the infected middle ear. From [9]. Permission obtained from Elsevier.