Enhanced Permeation of Methotrexate In Vitro by Ion Pair Formation With L-Arginine

Ion paired solutions of methotrexate in L-arginine/water/propylene glycol systems were evaluated for their potential to enhance the permeation of methotrexate across rabbit nasal mucosa in vitro. The partition coefficient of methotrexate in the methotrexate: L-arginine ion paired systems was observed to be 24 times greater than that of the methotrexate system without L-arginine. The ion pair formation between methotrexate and L-arginine was confirmed by a decrease in the conductivity of the systems in the presence of propylene glycol, a dielectric constant reducing agent. The permeation of methotrexate across the rabbit nasal mucosa from the ion paired systems was observed to be significantly greater (p < 0.05) as compared to control systems of methotrexate solution in water and a sodium salt. Furthermore, a threefold increase in the flux of methotrexate was observed when propylene glycol was added to the ion paired systems. These results suggest that methotrexate: L-arginine ion paired systems have potential in improving the permeation of methotrexate across rabbit nasal mucosa and may form the basis for further development of an intranasal therapeutic system of methotrexate. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3633–3639, 2009