Chem. Pharm. Bull. 53(8) 893—898 (2005)

etable oil that is emulsified with lecithin, and the droplet size generally ranges from 200—300 nm. They were originally introduced to provide a source of calories for patients unable to ingest food. Over the 20 years, extensive researches on their use for drug delivery systems have been reported. Reasons for using lipid emulsions as a drug carrier include: solubilization of low water-solubility drugs; stabilization of hydrolytically susceptible compounds; reduction of toxicity of intravenously administered drugs; potential for sustained release dosage forms; possible directed drug delivery to various organs and etc. Examples of marked formulations are intravenous emulsions with diazepam, prostaglandin E1 4) or a-tocopherol. Many workers have mainly chosen oil-soluble drugs for lipid emulsions formulation, while little has been paid attention for ionized drugs. Ionized drugs will possibly be adsorbed, at least partly, to the droplet interface which may contribute to the stability of the drugs. Physostigmine salicylate may be one example where the drug was adsorbed at the interface in the emulsions and was protected from the aqueous decomposition. The stability of ionized drugs and salts in lipid emulsions has been reported recently. However, studies mainly concerned about destablization of the mixture under the autoclaved condition. Gabexate mesilate (GM) and camostat mesilate (CM) are chemically ionized drugs and are clinically protease inhibitors currently available to inhibit the biological activities of plasma kallikrein, thrombin, plasmin and trypsin. They have been used for the treatment of pancreatitis. Ohkoshi et al. have been engaging in the research of anticancer effect of these protease inhibitors since the middle of the 1970’s. The drugs are thought to inhibit cell-surface enzymatic activity and the cell-to-cell contact, and prevent metastasis of cancer cells. Different from conventional anticancer agents, they are found to be non-cytotoxic. However due to their ionization property at physiological pH, these inhibitors suffer from low membrane permeability, high protein binding in blood, rapid elimination from plasma and etc. In their clinical anticancer trial, Ohkoshi et al. reported that frequent and long-term administration (at least for 6 weeks) was necessary for CM to maintain therapeutic blood level and to show its effect. With the aim of improving the therapeutic efficiency of GM and CM, we investigated the lipid emulsions (20% fractionated soybean oil) as a possible drug carrier for these protease inhibitors in terms of physicochemical interaction because of their structural characteristics: a relatively long hydrophobic moiety with a cationic guanidino group at the end. The distribution of GM and CM in the lipid emulsions was first examined. Subsequently, to interpret the distribution behavior of the two drugs at the oil droplet interface, surface potential changes and fluorescence changes were examined in addition to thermodynamics of the interaction.