Safety Aspects of Non-ionic Surfactant Vesicles: A Toxicity Study Related to the Physicochemical Characteristics of Non-ionic Surfactants

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Abstract
Two different toxicity models were used to assess the relationship between the physicochemical properties of non-ionic surfactant vesicles (NSVs), and the safety of these vesicles for topical drug administration. The vesicles used in this study consisted of polyoxyethylene alkyl ethers (CnEOm) in which the number of C atoms (n) varied between 12 and 18 and the number of oxyethylene units (m) between 3 and 7. The physicochemical properties of the vesicles are described in terms of hydrophilic-lipophilic balance (HLB) values, and critical micelle concentrations (CMC), and the rigidity of the bilayers as determined by the gel-liquid transition temperatures and the cholesterol content of the bilayers. The first toxicity model, comprising the measurement of the ciliary beat frequency, is a tool to assess the safety of intranasally applied formulations. Studies using this ciliotoxicity model revealed that by increasing the length of the alkyl chain of the surfactant, a decrease in toxicity was observed. The opposite correlation was found if the length of the polyoxyethylene headgroup was increased. Furthermore, it was observed that gel-state vesicles produce less of an effect on the ciliary beat frequency than liquid state vesicles. The second toxicity model, comprising the determination of cell proliferation of human keratinocytes, is a method to assess skin irritancy. In contrast to the ciliotoxicity model the length of the polyoxyethylene headgroup and of the alkyl chains did not seem to have an effect on the safety of the vesicles. However, the bond by which the headgroup is linked to the alkyl chain, showed a very strong effect on the toxicity of the surfactant: oleyl-EO5 ester vesicles were found to have an effect on the cell proliferation, which was one-sixteenth that of the oleyl-EO5 ether vesicles. The cholesterol content did not appear to have an effect on the proliferation of the keratinocytes. Neither the HLB nor the CMC values appeared to have an effect on the safety of the NSV formulations as observed in both toxicity models.