title: Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma concentrations for the treatment of autoimmune diseases.
abstract: Stichodactyla helianthus neurotoxin (ShK) is an immunomodulatory peptide currently under development for the treatment of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis by parenteral administration. To overcome the low patient compliance of conventional self-injections, we have investigated the potential of the buccal mucosa as an alternative delivery route for ShK both in vitro and in vivo. After application of fluorescent 5-Fam-ShK to untreated porcine buccal mucosa, there was no detectable peptide in the receptor chamber using an in vitro Ussing chamber model. However, the addition of the surfactants sodium taurodeoxycholate hydrate or cetrimide, and formulation of ShK in a chitosan mucoadhesive gel, led to 0.05-0.13% and 1.1% of the applied dose, respectively, appearing in the receptor chamber over 5h. Moreover, confocal microscopic studies demonstrated significantly enhanced buccal mucosal retention of the peptide (measured by mucosal fluorescence associated with 5-Fam-ShK) when enhancement strategies were employed. Administration of 5-Fam-ShK to mice (10mg/kg in a mucoadhesive chitosan-based gel (3%, w/v) with or without cetrimide (5%, w/w)) resulted in average plasma concentrations of 2.6-16.2nM between 2 and 6h, which were substantially higher than the pM concentrations required for therapeutic activity. This study demonstrated that the buccal mucosa is a promising administration route for the systemic delivery of ShK for the treatment of autoimmune diseases.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Boyd
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: White
authors.affiliation: Peptides International, Louisville, KY, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. Electronic address: joseph.nicolazzo@monash.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Nicolazzo
mesh_terms: D058956:Administration, Mucosal; D000818:Animals; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy*; D003064:Cnidarian Venoms / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D066298:In Vitro Techniques; D051379:Mice; D009061:Mouth Mucosa; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012015:Reference Standards; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D013657:Taurodeoxycholic Acid / Q000494:pharmacology
chemical_list: D003064:Cnidarian Venoms; D005456:Fluorescent Dyes; D007155:Immunologic Factors; D010455:Peptides; D013501:Surface-Active Agents; C059713:neurotoxin I, Stichodactyla helianthus; D013657:Taurodeoxycholic Acid
keywords: Autoimmune diseases; Bile salts; Buccal mucosa; Chitosan; Permeation