title: Therapeutic utility of a novel tight junction modulating peptide for enhancing intranasal drug delivery.
abstract: Previously, a novel tight junction modulating (TJM) peptide was described affording a transient, reversible lowering of transepithelial electrical resistance (TER) in an in vitro model of nasal epithelial tissue. In the current report, this peptide has been further evaluated for utility as an excipient in transepithelial drug formulations. Chemical stability was optimal at neutral to acidic pH when stored at or below room temperature, conditions relevant to therapeutic formulations. The TJM peptide was tested in the in vitro tissue model for potential to enhance permeation of a low-molecular-weight (LMW) drug, namely the acetylcholinesterase inhibitor galantamine, as well as three peptides, salmon calcitonin, parathyroid hormone 1-34 (PTH(1-34)), and peptide YY 3-36 (PYY(3-36)). In all cases, the TJM peptide afforded a dramatic improvement in drug permeation across epithelial tissue. In addition, a formulation containing PYY(3-36) and TJM peptide was dosed intranasally in rabbits, resulting in a dramatic increase in bioavailability. The TJM peptide was as or more effective in enhancing PYY(3-36) permeation in vivo at a 1000-fold lower molar concentration compared to using LMW enhancers. Based on these in vitro and in vivo data, the novel TJM peptide represents a promising advancement in intranasal formulation development.
authors.affiliation: Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA, USA.
authors.forename: Shu-Chih
authors.initials: SC
authors.lastname: Chen
authors.forename: Kristine
authors.initials: K
authors.lastname: Eiting
authors.forename: Kunyuan
authors.initials: K
authors.lastname: Cui
authors.forename: Alexis Kays
authors.initials: AK
authors.lastname: Leonard
authors.forename: Daniel
authors.initials: D
authors.lastname: Morris
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Li
authors.forename: Ken
authors.initials: K
authors.lastname: Farber
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Sileno
authors.forename: Michael E
authors.initials: ME
authors.lastname: Houston
authors.forename: Paul H
authors.initials: PH
authors.lastname: Johnson
authors.forename: Steven C
authors.initials: SC
authors.lastname: Quay
authors.forename: Henry R
authors.initials: HR
authors.lastname: Costantino
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002116:Calcitonin / Q000008:administration & dosage / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D004355:Drug Stability; D017097:Electric Impedance; D004847:Epithelial Cells / Q000378:metabolism; D005702:Galantamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics; D019894:Peptide YY / Q000008:administration & dosage / Q000493:pharmacokinetics; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D010539:Permeability; D011817:Rabbits; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: D010281:Parathyroid Hormone; D010446:Peptide Fragments; D010455:Peptides; D005702:Galantamine; D019894:Peptide YY; C061785:peptide YY (3-36); C028815:salmon calcitonin; D002116:Calcitonin