Absorption enhancement of poorly absorbed hydrophilic compounds from various mucosal sites by combination of mucolytic agent and non-ionic surfactant

Absorption enhancement of poorly absorbed hydrophilic compounds from various mucosal sites by co-administration of a mucolytic agent and a non-ionic surfactant was examined in rats. Fluorescein isothiocyanate-labeled dextran with average molecular weight of ca. 4.4 kDa (FD-4), and salmon calcitonin (SCT) were used as model compounds. N-acetylcysteine (NAC) and p-t-octyl phenol polyoxyethylene-9.5 (Triton X®-100, TX-100) were selected as a mucolytic agent and a non-ionic surfactant, respectively. Dosing solutions containing these agents were administered into various mucosal sites including the nose, the lung and the large intestine, and the bioavailabilities were determined. The combination of 5% NAC and 5% TX-100 significantly enhanced the nasal, the pulmonary and the large intestinal absorption of FD-4 compared to the control, and the enhancement ratios relative to the control were 7.2-, 2.8- and 4.5-fold, respectively. The different enhancement ratio among the administration sites explored indicates that the absorption enhancing effect of the combination of NAC and TX-100 is site-dependent. This combination also improved the nasal and the pulmonary absorption of SCT, and the enhancement ratios relative to the control were 6.1- and 8.1-fold, respectively. All these results suggest that the combination strategy of a mucolytic agent and a non-ionic surfactant may be widely applicable to various mucosal deliveries of poorly absorbed hydrophilic compounds.