title: Thiolated polycarbophil as an adjuvant for permeation enhancement in nasal delivery of antisense oligonucleotides.
abstract: The purpose of this study was to investigate the effect of thiolated polycarbophil as an adjuvant to enhance the permeation and improve the stability of a phosphorothioate antisense oligonucleotide (PTO-ODN) on the nasal mucosa. Polycarbophil-cysteine (PCP-Cys) was synthesized by the covalent attachment of L-cysteine to the polymeric backbone. Cytotoxicity tests were examined on human nasal epithelial cells from surgery of nasal polyps confirmed by histological studies. Deoxyribonuclease I activity in respiratory region of the porcine nasal cavity was analyzed by an enzymatic assay. The enzymatic degradation of PTO-ODNs on freshly excised porcine nasal mucosa was analyzed and protection of PCP-cysteine toward DNase I degradation was evaluated. Permeation studies were performed in Ussing-type diffusion chambers. PCP-Cys/GSH did not arise a remarkable mortal effect. Porcine respiratory mucosa was shown to possess nuclease activity corresponding to 0.69 Kunitz units/mL. PTO-ODNs were degraded by incubation with nasal mucosa. In the presence of 0.45% thiolated polycarbophil and 0.5% glutathione (GSH), this degradation process could be lowered. In the presence of thiolated polycarbophil and GSH the uptake of PTO-ODNs from the nasal mucosa was 1.7-fold improved. According to these results thiolated polycarbophil/GSH might be a promising excipient for nasal administration of PTO-ODNs.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 52, Josef Möller Haus, 6020 Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Vetter
authors.forename: R
authors.initials: R
authors.lastname: Martien
authors.forename: A
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000180:Acrylic Resins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage / Q000494:pharmacology*; D000281:Administration, Intranasal; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003545:Cysteine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D003850:Deoxyribonuclease I / Q000037:antagonists & inhibitors; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry; D004355:Drug Stability; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D009297:Nasal Mucosa / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010539:Permeability; D054735:Phosphorothioate Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011108:Polymers / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D013552:Swine
chemical_list: D000180:Acrylic Resins; D000277:Adjuvants, Pharmaceutic; D004337:Drug Carriers; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D011108:Polymers; C030312:calcium polycarbophil; D003850:Deoxyribonuclease I; D005978:Glutathione; D003545:Cysteine