Thiolated Polycarbophil as an Adjuvant for Permeation Enhancement in Nasal Delivery of Antisense Oligonucleotides

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. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1427–1439, 2010