The effects of i.v. formulations on the pharmacokinetics were examined for two antitumor agents with different lipophilicities: rhizoxin and palmitoyl-rhizoxin (RS-1541). Blood disposition and tissue distributions in rats were evaluated using three formulations: polyethylene glycol 400 (PEG)/dimethylacetamide (DMA) solution, colloidal solution, and lipid emulsions composed of dioctanoyl decanoyl glycerol (ODO) and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60). The effects of emulsion particle size on the pharmacokinetics were also investigated. Rhizoxin rapidly disappeared from the plasma and showed high distribution in the tissues, and in vitro rapidly degraded in the plasma independent of the formulations used. In in vitro plasma, rhizoxin was easily released from the emulsion particles. In contrast to rhizoxin, the pharmacokinetics of RS-1541 with greater lipophilicity changed considerably depending on the formulations. The emulsions showed high and sustained plasma concentrations for RS-1541. RS-1541 was stably incorporated in the emulsion droplets and protected from the degradation when it was applied as an emulsion. Tissue distributions of RS-1541 in rats after an injection as lipid emulsion were strongly affected by the emulsion particle size. Small size emulsions (100-110 nm) showed the highest plasma concentrations of RS-1541, though they were unable to suppress distributions of the drug in peripheral tissues. Emulsions larger than 200 nm (approx.) in size, on the contrary, effectively inhibited the drug from entering the bone marrow, small intestine and other non-reticuloendothelial system (non-RES) organs, where many cytotoxic compounds showed undesired toxicities. These results indicate that the lipid emulsions composed of ODO and HCO-60 could be a promising and effective DDS carrier for RS-1541, which is highly lipophilic and stabilized in the emulsions. This was not the case for rhizoxin, however, which was less lipophilic than palmitoyl analogue RS-1541. The work described herein has demonstrated that by properly selecting the particle size, these lipid emulsions can control the behavior of a drug in the body.

Four types of lipid emulsion for highly lipophilic antitumour agent RS‐1541 (13‐O‐palmitoylrhizoxin) with mean particle diameters of 200‐‐260 nm were prepared using soybean oil (SOY) or dioctanoyldecanoylglycerol (ODO) for the oil phase and lecithin (LEC) or polyoxyethylene‐(60)‐hydrogenated castor oil (HCO‐60) for surfactants. The lipolysis rate of HCO‐60‐emulsified emulsions by lipoprotein lipase was much slower than that of LEC‐emulsified emulsions. Particle sizes of emulsions incubated in plasma with the lipase for six hours were 75%, 79%, 101%, and 93% of initial values for SOY/LEC, ODO/LEC, SOY/HCO‐60, and ODO/HCO‐60 emulsions, respectively, showing an apparent size decrease for LEC‐emulsified emulsions. In rats, uptake clearance values of SOY/LEC and ODO/LEC emulsions of RS‐1541 in the reticuloendothelial system (RES) were 81·2 and 135·3 mL h−1, respectively, and AUC values were 4·0 and 1·3 μ g h mL−1, respectively. In contrast, RES uptake clearances of HCO‐60 emulsions of RS‐1541 were considerably lower (4·2 mL h−1 for SOY/HCO‐60; 2·2 mL h−1 for ODO/HCO‐60), resulting in high AUC values (35·4 μ g h mL−1 for SOY/HCO‐60; 63·9 μ g h mL−1 for ODO/HCO‐60). The concentrations of RS‐1541 in tumour tissues after an intravenous administration of ODO/HCO‐60 emulsions of RS‐1541 to mice bearing solid tumour M5076 sarcoma were about ten times higher than those after the administration of SOY/LEC emulsions. These results indicate that HCO‐60 emulsions, compared with conventional LEC emulsions, are more stable to lipoprotein lipase and show low uptakes by RES organs, long circulations in the plasma, and high distributions in tumours. Thus, these sterically stabilized emulsions could show potential as effective carriers for highly lipophilic antitumour agents to enhance the drug delivery in tumours.

When particle size is properly selected, these emulsions could be promising and effective as an injectable carrier for lipophilic antitumor agents in order to enhance the tumor delivery and efficacies while reducing toxicities.