Paracellular delivery of peptides—a rational approach

A review of research done on non-parenteral delivery of peptides

Aditya Pattani and Manan Desai

The tremendous growth in the biotechnology industry has provided the production facility for many drugs. About a quarter of all the drug approvals in USA and Europe between 2002 and 2003 are biopharmaceuticals. These drugs hold the potential to treat diseases, which otherwise cannot be treated with conventional drugs. This technology has now enabled drug technologist to manufacture these drugs on a larger scale in safe, effective, and easy to use dosage forms is possible.

Most biopharmaceuticals products belong to the peptide class. These drugs present a unique challenge to drug delivery technologists. They differ fundamentally from the conventional drugs because they are extremely susceptible to both enzymatic and chemical degradation, and have a large molecular weight, high water solubility, and are very polar compared with the conventional drugs. Because of these properties the transcellular passive diffusion, the major route for the absorption of conventional drugs, cannot be utilised for the delivery of these peptides.

The need for non-parenteral delivery of peptides cannot be over emphasised. Much effort has been put into delivering peptides via oral routes. Other routes include colon specific delivery, buccal, nasal, transdermal, rectal, and iontophoretic delivery. Amongst dosage forms, mucoadhesive formulations have been tried. Among the colloidal carriers, polymeric, nanoparticles have been widely explored. In addition to having a large surface area, bioadhesive nanoparticles can adhere to the mucosa, such that they have increased contact time and within the nanoparticles the drug is protected from the proteolytic enzymes. Other colloidal carriers that have been tried are micro spheres, micelles, niosomes, and liposomes. In addition, proteolytic enzyme inhibitors have been shown to improve bioavailability. Polymer conjugates of the protease inhibitors have been used to increase the residence time of the inhibitor in the vicinity of the drug. Not only are the peptides susceptible to the proteases but also have a low permeability. It is well known that the peptides can maintain their structures in the presence of water only. When exposed to a hydrophobic environment, their hydrophobic residues get exposed and this results in the denaturation of the peptide.

Currently, a new route—the paracellular pathway—is being explored for delivery of peptides. As opposed to the transcellular pathway, the paracellular pathway is a water-filled pathway, which is amicable to the delivery of polar molecules like peptides and proteins.

Another advantage is that by traversing through the area between the two cells the peptide also circumvents the intracellular lysosomal enzymes.

A major problem is the low pore size of the paracellular pathway. It is now known that the pore size can be regulated by various cellular signaling pathways. Thus, studying the molecular physiology of the paracellular space may provide an answer to opening of the paracellular pathway.

Further studies have led to the development of various classes of paracellular penetration enhancers.—

• Cationic substances, including arginine, lysine and their polymers, cetyl pyrimedium chloride, and chitosan;
• Calcium modulators, including ethyl diamine tetra acetic acid, sodium caprate, and lauroyl carnitine, plamatoyl carnitine, and organic acids such as tartaric and citric acids
• Superporous hydrogels, which enhance the paracellular uptake either by chelating the Ca2+ ions or by an unknown mechanical process. However, their precise mechanism remains debatable
• Zonula occludens toxin, which is a toxin produced by vibrio cholerae, which regulates tight junctions that in turn regulate paracellular permeability
• Occludin peptides, which regulate tight junctions that in turn regulate paracellular permeability

We now understand the rationale behind using the paracellular pathway for delivering peptides. As molecular organisation and signaling pathways involved in control of paracellular permeability become clear, we will be able to identify newer and safer paracellular penetration enhancers. In years to come, paracellular delivery of proteins and peptides may become a clinical reality as it would be possible to design simple and easy to use dosage forms for non-parenteral delivery of proteins and peptides. z

(Aditya Pattani is currently associated with H(S)NCB's College of Pharmacy and was formerly with UICT, Mumbai. Manan Desai was formerly with Institute of Science, Mumbai)