Authors: Johnson, Paul H; Quay, Steven C

Source: Expert Opinion on Drug Delivery, Volume 2, Number 2, 1 March 2005 , pp. 281-298(18)

Publisher: Informa Healthcare

Abstract:

New approaches for enhancing intranasal drug delivery based on recent discoveries on the molecular biology of tight junctions (TJ) are significantly improving the bioavailability of ‘non-Lipinsky’ small molecules, and peptide, protein and oligonucleotide drugs. As knowledge of the structure and function of the TJ has developed, so has the ability to identify mechanism-based TJ modulators using high-throughput molecular biology-based screening methods. The present review focuses on recent developments on the TJ protein complex as a lipid raft-like membrane microdomain, the emerging role of unique endocytic pathways in regulating TJ dynamics, and the utility of techniques such as RNA interference and phage display to study TJ components and identify novel peptides and related molecules that can modulate their function. Experimental and statistical methodologies used for the identification of new classes of TJ modulators are described, which are capable of reversibly opening TJ barriers with broad potential to significantly improve intranasal and, eventually, oral drug delivery. The development of an advanced intranasal formulation for the obesity therapeutic PYY_3-36, the endogenous Y2 receptor agonist is also reviewed.

Keywords: calcium; claudin; design of experiments; E-cadherin; endocytosis; epithelium; formulation development; intranasal drug delivery; junctional adhesion molecule; lipid rafts; Lipinsky’s rule of five; obesity; occludin; paracellular transport; permeation assays; phage display; PYY3-36; RNA interference; tight junction; transepithelial electrical resistance

Document Type: Review article

DOI: http://dx.doi.org/10.1517/17425247.2.2.281

Publication date: 2005-03-01

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