title: Nasal drug delivery: Design of a novel mucoadhesive and in situ gelling polymer.
abstract: The aim of the present study was to establish a novel polymeric excipient for liquid nasal dosage forms exhibiting viscosity increasing properties, improved mucoadhesion and stability towards oxidation in solution. In order to achieve this goal, 2-mercaptonicotinic acid was first coupled to l-cysteine by disulfide exchange reaction and after purification directly attached to the polymeric backbone of xanthan gum by carbodiimide mediated amide bond formation. The resulting conjugate was characterized with respect to the amount of coupled ligand, the in situ gelling behavior, mucoadhesive properties and stability towards oxidation. Furthermore, the influence of preactivated polymers on ciliary beat frequency (CBF) of porcine nasal epithelial cells was investigated. Results showed, that 252.52±20.54μmol of the ligand was attached per gram polymer. No free thiol groups could be detected on the polymeric backbone indicating entire preactivation. Rheological investigations of polymer mucus mixtures revealed a 1.7-fold and 2.5-fold enhanced mucoadhesion of entirely preactivated xanthan (Xan-Cys-MNA) compared to thiolated xanthan (Xan-Cys) and unmodified xanthan (Xan). Tensile force evaluation reported a 2.87 and 5.11-fold higher total work of adhesion (TWA) as well as a 1.63 and 2.41-fold higher maximum detachement force of Xan-Cys-MNA compared to Xan-Cys and Xan. In the presence of H2O2as an oxidizing agent Xan-Cys-MNA showed unlike Xan-Cys no increase in viscosity, indicating high stability towards oxidation. Addition of CaCl2to Xan-Cys-MNA solutions caused a decrease in viscosity at nevertheless higher total viscosity. Results from CBF studies proved nasal safety for the novel conjugate. According to these results, entirely preactivated thiolated xanthan gum seems to be a promising excipient for nasal dosage forms in order to improve drug bioavailability.
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Menzel
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Max
authors.initials: M
authors.lastname: Jelkmann
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000269:Adhesives / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D002923:Cilia / Q000187:drug effects / Q000502:physiology; D003545:Cysteine / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D005079:Excipients; D009297:Nasal Mucosa / Q000187:drug effects / Q000502:physiology; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D013552:Swine; D013718:Tensile Strength; D014783:Viscosity
chemical_list: D000269:Adhesives; D005079:Excipients; D009539:Nicotinic Acids; D011108:Polymers; D011135:Polysaccharides, Bacterial; D013438:Sulfhydryl Compounds; C083470:2-mercaptonicotinic acid; D003545:Cysteine; C002563:xanthan gum
keywords: Disulfide exchange; In situ gelling polymer; Liquid dosage form; Mucoadhesion; Nasal drug delivery; Oxidation; Preactivated thiomers