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PEPTIDES AND PEGYLATED PEPTIDES AS INTRANASAL PERMEATION ENHANCERS: COMPARISON TO SMALL MOLECULAR EXCIPIENTS.
Lamharzi, N., Sileno, T., Eiting, K.T., Templin, M., Haugaard, K.D., Houston, M., Cui, K., Johnson, P.H., Chen, S-C.
Nastech Pharmaceutical Company, Inc., Bothell, Washington.
Journal of Pharmaceutical Sciences, 95, (6) 1364-1371 (2006).
Keywords: 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)
Endpoints: Apical lactate dehydrogenase cytoxicity assay, Cytotoxicity, ELISA assay, Endocytosis inhibition, MTT assay, Permeability assay, Transepithelial resistance (TER)
Materials Tested: , FITC-dectrans, Na-fluorein, Pegylated PN159 (peg-PN159)
Summary:
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.
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