Physical and chemical approaches to minimize the irritation potential of the spermicidal agent nonoxynol-9.

摘要

Reduction of the chemical irritation potential of the spermicidal agent nonoxynol-9 (N-9, n = 1--17) was studied through the synthesis of mono-iodinated derivatives and the production of coprecipitates with polyvinylpyrrolidone (PVP). Synthesis of mono-iodinated nonoxynol-9 (IN-9, n = 1--17) was accomplished with use of thallium (III) trifluoroacetate (TTFA). Iodinated derivatives were found to possess greater hydrophobic character compared to the starting material that led to lower critical micelle concentration (CMC) values. Oligomeric samples of N-9 and IN-9 were found to possess greater CMC values as the length of the ethylene oxide chain increased. Coprecipitates of N-9 (n = 1--17) or IN-9 (n = 1--17) with PVP were formed, which allowed for an increase in the CMC values of the spermicidal agents.;Chemical irritation potential measurements for N-9 (n = 1--17), IN-9 (n = 1--17) and structurally related surfactants were determined by use of a red blood cell (RBC) hemolysis assay. IN-9 samples were found to cause hemolysis at lower concentrations compared to similar N-9 samples. Nonoxynols with sufficiently long ethylene oxide chains were found to cause hemolysis at higher concentrations compared to N-9 (n = 1--17). Coprecipitates of N-9 (n = 1--17) or IN-9 (n = 1--17) with PVP were found to cause less hemolysis in the RBC model compared to neat compounds. Reductions in hemolysis indicated a decrease in the chemical irritation potential of the nonoxynols towards RBC membranes. Hemolysis was initiated at concentrations in which surfactant monomers began to self aggregate into micelles.;In the modified Sander-Cramer assay, samples of IN-9 (n = 1--17, 8--10, 11--14) possessed higher spermicidal activity compared to N-9 (n = 1--17). N-9 (n = 1--17)/PVP coprecipitates did not influence the spermicidal activity of the spermicidal agent. IN-9 (n = 1--17)/PVP coprecipitates were found to possess reduced spermicidal activity compared to neat samples of IN-9 (n = 1--17).;Biodistribution of [125I] IN-9 (n = 1--17) was found to be comparable to that of [14C] N-9 (n = 3--11) after six-hour post-vaginal administration in rats.