Enabling Noninvasive Systemic Delivery of the Kv1.3-Blocking Peptide HsTX1[R14A] via the Buccal Mucosa.
The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, a well-recognized therapeutic target for autoimmune diseases. To overcome the poor oral absorption and consequent need for regular injections, the potential of the buccal mucosa for systemic delivery of HsTX1[R14A] was investigated. For in vitro studies, FITC-HsTX1[R14A] and HsTX1[R14A], in solution or formulated in a mucoadhesive chitosan-based gel (3%, w/v) with or without cetrimide (5%, w/w), were applied to porcine buccal epithelium mounted between Ussing chambers and buccal mucosal permeation assessed. HsTX1[R14A] was also administered to Swiss outbred mice at a dose of 10 mg/kg in the same formulations. In vitro, administration of FITC-HsTX1[R14A] and HsTX1[R14A] in the chitosan gel containing cetrimide resulted in detectable buccal permeation with 0.75% and 0.58%, respectively, of the applied dose appearing in the receptor chamber over 5 h. After buccal administration to mice, HsTX1[R14A] was detected in plasma, with the presence of cetrimide in the gel further enhancing plasma exposure, with area under the plasma concentration-time curve values of 77.9 ± 9.7 and 31.0 ± 2.3 nM·h, respectively. The buccal mucosa is a promising alternative administration route for the systemic delivery of HsTX1[R14A] for the treatment of autoimmune diseases.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Liang
L
Jin
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Ben J
BJ
Boyd
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Ian C
IC
Larson
Peptides International, Louisville, Kentucky 40299.
Michael W
MW
Pennington
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Raymond S
RS
Norton
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: joseph.nicolazzo@monash.edu.
Joseph A
JA
Nicolazzo
D000278:Administration, Buccal; D000818:Animals; D000077286:Cetrimonium; D002593:Cetrimonium Compounds; D048271:Chitosan; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005079:Excipients; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D051379:Mice; D009061:Mouth Mucosa / Q000378:metabolism*; D010539:Permeability; D019999:Pharmaceutical Solutions; D026902:Potassium Channel Blockers / Q000008:administration & dosage*; D012604:Scorpion Venoms / Q000008:administration & dosage*; D013552:Swine; D014014:Tissue Adhesives
D002593:Cetrimonium Compounds; D005079:Excipients; D051664:Kv1.3 Potassium Channel; D019999:Pharmaceutical Solutions; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; C109471:TX1 toxin, Heterometrus spinnifer; D014014:Tissue Adhesives; D048271:Chitosan; D000077286:Cetrimonium
absorption; chitosan; mucosal delivery; peptides; permeability