Enhanced skin permeation of 6-methoxy-2-naphthylacetic acid by salt formation

The aim of this work was to prepare salts of 6-methoxy-2-naphthylacetic acid (6-MNA) to improve its physicochemical properties for percutaneous application. 6-MNA, an active metabolite of non-steroidal anti-inflammatory drug nabumetone has long half life and has the tendency to penetrate well into synovial fluid. The physicochemical properties of 6-MNA salts were investigated by solubility measurements, differential scanning calorimetry (DSC) and infrared (IR). The DSC thermograms and Fourier transform infrared (FT-IR) spectra indicated that 6-MNA formed salts with organic and alkali metal bases. Among the series, salts formed with amine bases (ethanolamine, diethanolamine, triethanolamine and diethylamine) had lower melting points while alkali metal salt (sodium) had higher melting point than 6-MNA. The salts had higher solubilities than 6-MNA as determined in phosphate buffer at pH 5.0 and 7.4. There is no significant difference in partition coefficient (log P) values between salts and 6-MNA at pH 5.0 but, at pH 7.4, the log P values for the salts increased by 4-10 times as compared to 6-MNA. In vitro permeation studies showed that all the salts increased the flux in comparision to 6-MNA, and the ethanolamine salt (1b) was found to be having 7.7 and 9.4 times higher permeability as compared to 6-MNA at pH 5.0 and 7.4, respectively.