Systemic absorption of insulin delivered via eyedrops has been studied in rats made transiently hyperglycemic by anesthesia with xylazine/ketamine. Insulin at a concentration of 2 mg/ml was not absorbed significantly when saline alone was used as the formulation for the eyedrops (0.04 ml). When various emulsant agents were added to the eyedrop formulation, systemic insulin levels were increased and concomitantly, blood D-glucose levels were decreased Saponin, Brij-78, BL-9 and several alkylglycosides all increased the systemic absorption of insulin following delivery in eyedrops. Not all surfactant agents were effective in promoting systemic insulin absorption from eyedrops, as evidenced by the failure of some non-ionic surfactants to increase insulin absorption. Similar results were obtained when nosedrops containing insulin plus non-ionic surfactants were administered to rats. In conclusion, systemic insulin absorption was greatly accelerated by the addition of certain emulsants to the eyedrop formulation and physiologically important levels of insulin could be delivered systemically following eyedrop administration. © 1994, Mary Ann Liebert, Inc. All rights reserved.