title: Thiolated chitosan nanoparticles for the nasal administration of leuprolide: bioavailability and pharmacokinetic characterization.
abstract: The purpose of this study was to develop thiolated nanoparticles to enhance the bioavailability for the nasal application of leuprolide. Thiolated chitosan-thioglycolic acid (chitosan-TGA) and unmodified chitosan nanoparticles (NPs) were developed via ionic gelation with tripolyphosphate (TPP). Leuprolide was incorporated during the formulation process of NPs. The thiolated (chitosan-TGA) NPs had a mean size of 252 ± 82 nm, a zeta potential of +10.9 ± 4 mV, and payload of leuprolide was 12 ± 2.8. Sustained release of leuprolide from thiolated NPs was demonstrated over 6h, which might be attributed to inter- and/or intramolecular disulfide formation within the NPs network. Ciliary beat frequency (CBF) study demonstrated that thiolated NPs can be considered as suitable additives for nasal drug delivery systems. Compared to leuprolide solution, unmodified NPs and thiolated NPs provoked increased leuprolide transport through porcine nasal mucosa by 2.0 and 5.2 folds, respectively. The results of a pharmacokinetic study in male Sprague-Dawley rats showed improved transport of leuprolide from thiolated NPs as compared to leuprolide solution. Thiolated NPs had a 6.9-fold increase in area under the curve, more than 4-fold increase in elimination half-life, and a ∼3.8-fold increase in maximum plasma concentration compared to nasal solution alone. The relative nasal bioavailability (versus s.c. injection) of leuprolide thiolated NPs calculated on the basis of AUC((0-6)) was about 19.6% as compared to leuprolide solution 2.8%. The enhanced bioavailability of leuprolide is likely due to facilitated transport by thiolated NPs rather than improved release.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 52c, Josef Möller Haus, 6020 Innsbruck, Austria.
authors.forename: Gul
authors.initials: G
authors.lastname: Shahnaz
authors.forename: Anja
authors.initials: A
authors.lastname: Vetter
authors.forename: Jan
authors.initials: J
authors.lastname: Barthelmes
authors.forename: Deni
authors.initials: D
authors.lastname: Rahmat
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.forename: Javed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Glen
authors.initials: G
authors.lastname: Perera
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schlocker
authors.forename: Sarah
authors.initials: S
authors.lastname: Dünnhaput
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods; D048271:Chitosan / Q000008:administration & dosage* / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006207:Half-Life; D006801:Humans; D016729:Leuprolide / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D009297:Nasal Mucosa / Q000378:metabolism; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013552:Swine; D013864:Thioglycolates / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D013438:Sulfhydryl Compounds; D013864:Thioglycolates; C017487:2-mercaptoacetate; D048271:Chitosan; D016729:Leuprolide