Prevention of molecular self-association by sodium salicylate: effect on insulin and 6-carboxyfluorescein.
The effect of sodium salicylate on the concentration-dependent self-association of insulin and 6-carboxyfluorescein (CF), as expressed by metachromasy, fluorescence, and changes in aqueous solubility, was learned. By decreasing the CF concentration from 12 to 0.48 microgram.ml-1, lambda max peaks shift from the shorter wavelengths (451, 474 nm), indicating the presence of oligomers, toward the monomer wavelength region (484 nm). Sodium salicylate shifts the peaks of a 12 micrograms.mL-1 CF solution towards the monomer region, eliminating the peak at the lower wavelengths and generating a spectrum with one peak at 490 nm, the effect being concentration dependent. The fluorescence of insulin and CF solutions increases with their concentration. Quenching of these solutions was observed, up to complete elimination of fluorescence, when various concentrations of salicylate were added. The water solubility of both molecules, CF and insulin, was considerably increased with the addition of increasing concentrations of salicylate to the solutions: at 37 degrees C, 2.5 M sodium salicylate solution increases the CF solubility 532 times from 12.2 to 6.5 mg.mL-1, and 1.5 M salicylate increases the solubility of insulin 7875 times, thus an aqueous solution containing 630 mg.mL-1 of insulin may be prepared. The results obtained here, together with our previously reported data, indicate that the interference between sodium salicylate and drug self-association behavior, by increasing drug solubility, may substantially contribute to the improved drug bioavailability mediated by salicylate.
Touitou
E
E
School of Pharmacy, Hebrew University of Jerusalem, Israel.
Alhaique
F
F
Fisher
P
P
Memoli
A
A
Riccieri
F M
FM
Santucci
E
E
D002626:Chemistry, Pharmaceutical; D005452:Fluoresceins / Q000032:analysis*; D007328:Insulin / Q000032:analysis*; D012980:Sodium Salicylate / Q000032:analysis*; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013053:Spectrophotometry; D013056:Spectrophotometry, Ultraviolet
D005452:Fluoresceins; D007328:Insulin; C024098:6-carboxyfluorescein; D012980:Sodium Salicylate