Combining esters of para-hydroxy benzoic acid (parabens) to achieve increased antimicrobial activity

Abstract

Lower alkyl esters of p-hydroxy benzoic acid (parabens) are widely used as preservatives of pharmaceuticals, cosmetics and allied products. Microbial activity increases with increasing alkyl chain length for the commonly used methyl, ethyl, propyl and butyl parabens, and synergy between parabens has been reported. However, although generally giving lower MIC values, greater toxicity issues seem to be associated with the larger parabens. Each of these observations is important in deciding how parabens should be combined to achieve best protection of the product in question, whilst minimizing the health risk to the user. The present study combined methyl (M)-, ethyl (E)-, propyl (P)- and butyl (B)-parabens in a matrix analysis to identify combinations of two or more parabens showing promising activity against microbes in vitro. Five particularly efficacious combinations were defined. Two of these were compared with a standard mixture of all four parabens widely used in the production of medicinals in Norway. Activities against a number of microbes in vitro, and in situ when included in an ophthalmic and a topical preparation were investigated. The novel combinations performed as well or better than the standard mixture in all tests when present at the same total paraben concentration. Two of the novel mixtures achieved in most tests a greater antimicrobial effect in vitro than a commonly used mixture at 50% of the total paraben concentration. It is concluded that the novel paraben mixtures 47% M, 23.5% E, 6.0% P, 23.5% B and 44.5% M, 44.5% P, 11.0% B at 0.05-0.1% w/v represent improvements on the widely used combination 50% M, 35% E, 10% P, 5% B within the framework of the current tests, and should be considered as alternatives.