Summary And Future Directions

Some of the earliest permeation enhancers, including surfactants such as sodium dodecyl sulfate and bile salts, have shown limited success at enhancing delivery of peptides and proteins, and it appears that there is a direct correlation between potency and local toxicity [for review, see Johnson and Quay (75)]. Efforts to develop the next generation of IN permeation enhancers have focused on maximizing permeation and controlling PK of macromolecular drugs such as peptides and proteins while minimizing local toxicity. Recently, a systematic screen of surfactants identified concentrations that were both safe and efficacious (116,117), suggesting that a better understanding of the structure-function relationships for this category of enhancers may yield useful permeation enhancers. Further, by optimizing combinations and concentrations, a new repertoire of synergistic enhancer formulations were identified that improved performance without increasing toxicity in in vitro Caco-2 cell model (118).

Recent studies have revealed that TJs are not static but undergo continual remodeling with ZO-1, occludin and claudin entering and leaving the junction with distinct dynamic behavior (119). These findings open up the possibility of rapid TJ remodeling by permeation enhancers that target the functional domains of the junctional proteins or by affecting signaling through pathways that regulate TJ assembly and disassembly. For instance, cholesterol-solubilizing agents have been shown to increase paracellular permeability, possibly through release of lipid-derived second messengers, which could affect the phosphorylation state of TJ proteins (120). More recently, Chen-Quay et al. (121) developed a screen to identify lipids that modulated TJ properties. Lipids from three structural groups were identified (glycosylated sphingosines, oxidized lipids, and ether lipids) that rapidly and reversibly reduced TER by up to 95% and enhanced permeation of 3-kDa dextran with minimal toxicity. The identified lipids are present in lipid raft domains in cell membranes, which have been shown to be sites of TJ assembly. Therefore, it is possible that in addition to more direct effects on signaling pathways, perturbation of local membrane domains could promote TJ disassembly or endocytosis.

Peptide-based permeation enhancers are attractive candidates as they share physiochemical, diffusion, and release properties at the epithelial surface with peptide and protein drugs. Most peptide enhancers, such as zonula occluden toxin (Zot), have been described for oral drug delivery [for review see Maher et al. (122)], with few studies existing for nasal delivery. Attempts to design peptides that competitively bind to extracellular domains of occludin or claudins and thus disrupt TJ assembly demonstrate some promise (123-125). For instance, Mrsny et al. (126) have identified a critical claudin-1 extracellular loop motif that increased paracellular gastric permeability when administered orally to rats (126). As another example, Chen et al. (109) have described an 18-amino acid amphipathic peptide, PN159, capable of reducing TER and increasing permeation of peptide drugs with low toxicity in primary bronchial/tracheal cell cultures. Further, in vivo studies of intranasally dosed rabbits demonstrated PN159 increased permeation of PYY3-36 by 50 to 70 fold. PN159 was shown to be chemically stable under storage conditions relevant to IN formulations. These results demonstrate that such peptide enhancers have utility for enhancing nasal delivery of peptide drugs.

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