Better GRAS than sorry: Excipient toxicity in pulmonary formulations

Similar to other routes of administration, pulmonary formulations typically contain excipients. The panel of substances that can be used in pulmonary formulations is limited compared to other routes of administration, and most of them have the generally regarded as safe (GRAS) status. New excipients must undergo in vitro and complete in vivo testing to be approved by regulatory authorities. The toxic effects induced by excipients contained in the most common pulmonary formulations (dry powder inhalers, pressurized metered dose inhalers, and nebulizers) were summarized to compare the cytotoxic effects to the approved concentrations. The hypothesis was that a concentration much higher than the approved one could serve as an indicator of the safety of the compound. While the cytotoxic concentration of many excipients was higher than the approved concentration, the opposite was found for some of them. For most of these compounds, adverse lung effects were reported with long-term administration or in specific populations. This suggests that concentrations lower than the cytotoxic threshold are unlikely to cause adverse respiratory effects. Combining excipients can increase toxic effects, but few studies address this. Since neither cytotoxicity testing nor animal testing can reliably identify toxic concentrations of excipients, additional in vitro tests have been proposed.