PEPTIDES AND PEGYLATED PEPTIDES AS INTRANASAL PERMEATION ENHANCERS: COMPARISON TO SMALL MOLECULAR EXCIPIENTS.

This study by scientists at Nastech Pharmaceuticals demonstrated how MatTek’s EpiAirway human tracheal/bronchial tissue equivalent can be used to identify novel permeation enhancers for use in nasal drug delivery. Intranasal delivery as an alternative route for administering drugs, in particular biologically active peptides, is desirable. Earlier studies by Nastech Pharmaceutical Company scientists showed that a peptide-based permeation enhancer, PN159 increased the in vitro and in vivo permeation of a 34-amino acid hormone (used as a model payload) to a similar degree as a formulation based on small molecule excipients (SME). In this study, Nastech scientists investigated if pegylation of PN159 enhances permeation in vitro and/or in vivo. A bronchial/tracheal epithelial (EpiAirway) tissue was used to monitor transepithelial resistance (TER), permeability and cytotoxicity of the SME, PN159 and pegylated PN159 (peg-PN159) formulations in vitro. In addition, a plasma pharmacokinetic study was conducted in the rabbit after intranasal administration of formulations containing SME, PN159 or peg-PN159. Results showed that PN159 and peg-PN159 dramatically reduced TER and increased permeation of FITC-dextran 3000 at concentrations as low as 12.5 uM. There was a minimal effect on viability after 1h incubation with increasing concentrations of the peptides with and without pegylation. Endocytosis inhibition studies showed that the effect of PN159 and peg-PN159 on permeability is temperature- and energy-dependent, but does not involve clathrin or macropinocytosis. Permeation enhancement by pegylated-PN159 in EpiAirway tissues was 1.2 fold greater than SME and 10 fold greater than PBS. Pharmacokinetic studies showed that when evaluating Cmax, permeation enhancement by peg-PN159 was 1.9 fold higher than SME and 13.6 fold greater than PBS. When evaluating AUClast, permeation enhancement by peg-PN159 was 1.4 fold higher than the SME and 15.1 fold greater than PBS. There was a significant difference between peg-PN159 and the PBS formulation when comparing pharmacokinetic parameters, Cmax and AUC. In conclusion, Nastech scientists demonstrated that pegylated peptides such as peg-PN159 show significant potential as permeation enhancers for nasal drug delivery in EpiAirway-based experiments.

Biologically active peptides, Bronchial/tracheal epithelial tissue, EpiAirway, Intranasal delivery, Intranasal permeation enhancers, Muco-cilated tissue model, Nasal drug delivery, Pegylated peptide, Peptide, Peptide-based permeation enhancer, Permeation enhancer, Plasma pharmacokinetic study, Small molecule excipients (SME)

FITC-dectrans, Na-fluorein, Pegylated PN159 (peg-PN159)