Ionic interaction of amiloride and uridine 5′-triphosphate in nebulizer solutions

Abstract

Combination therapy using nebulized amiloride hydrochloride and uridine-5′-triphosphate (UTP) trisodium salt aerosols has been investigated for the treatment of cystic fibrosis (CF). Amiloride in aqueous solution precipitates in the presence of UTP, reducing drug concentrations. Interactions between these drugs and NaCl in solution were studied using phase-solubility techniques monitored by UV spectrophotometry. Elemental analyses were employed for precipitate characterization. Amiloride solubility was reduced by more than 85% in saline. Amiloride solubility decreased with increasing UTP concentration, resulting in formation of a precipitated complex. The theoreticalmolar ratio of complexes range from 1−3 amiloride:1 UTP. At most concentrations only 3 amiloride:1 UTP complex was observed in precipitate. This is a reflection of low Ksp for the 3:1 complex of 2.92×10−11 M4 compared with 2.09×10−4 M2 for amiloride alone. Equilibration over excess bulk solid resulted in higher solubility estimates and different phase solubility diagrams than solubility studies utilizing precipitation technique. This may be explained by the absence of amiloride in the solid state and its impact on complex equilibria with UTP. The solubility suppressing effects of UTP and saline were largely additive. A number of ionic interactions increase complex solubility profile of amiloride hydrochloride in the presence of UTP and NaCl.