title: The influence of stabilizer and bioadhesive polymer on the permeation-enhancing effect of AT1002 in the nasal delivery of a paracellular marker.
abstract: Permeation enhancers are of major interest to improve the low bioavailability of therapeutic agents due to poor membrane permeation. AT1002, a six-amino acid fragment of Zonula occludens toxin, was reported to possess permeation-enhancing effects. However, further studies were suggested to focus on the peptide nature of AT1002 like stability and membrane clearance to accurately reflect its permeation-enhancing potential. Thus, this paper focused on the susceptibility of AT1002 for identifying additives to minimize the instability of AT1002, and the permeation-enhancing effect of AT1002 when co-administered with a bioadhesive polymer. The stability study showed that AT1002 were unstable in neutral to basic pH conditions and with increasing incubation time, and 5% dextrose and the 1% mixture of amino acids (arginine, cysteine, glycine) significantly minimized the instability of AT1002 at pH 7.4 for at least 6 hours, respectively. In the intranasal study of a paracellular marker, the administration of mannitol with AT1002 in 5% dextrose solution led to statistically significant 3.14- and 2.17-fold increases in C(max) and AUC(0-360min) in the presence of carrageenan over the control. Thus, the addition of carrageenan as a bioadhesive polymer and dextrose as a stabilizer together with AT1002 may allow the development of the mucosal drug delivery of low-bioavailability therapeutic agents.
authors.affiliation: Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Science, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA. beophyen@snu.ac.kr
authors.forename: Keon-Hyoung
authors.initials: KH
authors.lastname: Song
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Eddington
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001120:Arginine / Q000737:chemistry; D001682:Biological Availability; D002351:Carrageenan / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D003545:Cysteine / Q000737:chemistry; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D005947:Glucose / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D008297:Male; D008353:Mannitol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D011108:Polymers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014014:Tissue Adhesives / Q000494:pharmacology*
chemical_list: C530561:AT1002; D005079:Excipients; D009842:Oligopeptides; D011108:Polymers; D014014:Tissue Adhesives; D008353:Mannitol; D002351:Carrageenan; D001120:Arginine; D005947:Glucose; D003545:Cysteine; D005998:Glycine