Physicochemical determinants of nasal drug absorption

Abstract

Intranasal absorption has been demonstrated for various drugs, including peptidic compounds, under a wide range of delivery conditions. However, little is known of the physicochemical nature of the nasal mucosal membrane and how specific changes in the nasal microenvironment affect molecular transport. Using a modification of a previously reported ex vivo rat flow circuit model, we studied the nasal uptake of a series of alkanoic acids, alcohols, and steroids to determine the effects of pH, buffers, molecular size, and lipophilic/hydrophilic characteristics on nasal mucosal membrane transport. Nasal absorption was evaluated by measuring the rate of disappearance of radiolabeled test compounds from a recirculating bath. The uptake of each compound by flow circuit components was assessed prior to the animal studies to minimize system artifacts. Our preliminary results indicate that nasal membrane integrity is preserved for at least one hour in the ex vivo recirculation system. The absorption rates for decanoic, octanoic and hexanoic acids were pH dependent, reaching a maximum at pH 4.5, and steadily decreasing at more acidic or basic pH values. Further, the temporal pattern of the absorption profiles for the alkanoic acids was also pH dependent. Nasal absorption of mannitol was negligible, whereas, rate of uptake of steroid drugs was related to lipophilic/hydrophilic character and was pH independent. These findings suggest that for nonionized molecules, the nasal mucosal membrane is essentially a modified lipophilic transport barrier without obvious evidence of aqueous pores. Further, due to the complex architecture offered by the nasal passages, and the presence of a multicomponent overlying mucus layer, boundary layer mixing effects and microenvironmental pH may influence transport of charged species.