O/W lipid emulsions for parenteral drug delivery. III. Lipophilicity necessary for incorporation in oil particles even after intravenous injection.

The potential usefulness of oil-in-water (O/W) lipid emulsions as injectable drug delivery systems was examined. Plasma concentrations of oil particles after intravenous injection of a standard lipid emulsion composed of soybean oil and egg yolk phosphatides were monitored based on the plasma concentrations of phospholipids and triglycerides, and the light scattering intensity of the plasma. Their time profiles were similar to each other, and the oil particle size decreased time-dependently. Pretreatment with dextran sulfate, a known reticuloendothelial system (RES) suppressor, resulted in marked reduction of the plasma clearance of the oil particles and of the time-dependent alteration of oil particle size, suggesting that oil particles were trapped by RES. The lipophilicity of the drug needed for its incorporation in the oil particles even after intravenous injection was found to be clog P > 8, where clog P is the calculated logarithm of the partition coefficient between n-octanol and water. In the case of sudan II (clog P = 5.4), the release from the oil particles was very quick after intravenous injection, resulting in slight alteration in biodistribution when compared with its micellar solution. In contrast, menatetrenone (clog P = 9.5) was selectively delivered to the liver, lungs and spleen, being consistent with the oil particles taken up by RES.

Effect of composition on biological fate of oil particles after intravenous injection of O/W lipid emulsions.

Plasma concentrations of oil particles after intravenous injection of oil-in-water (O/W) lipid emulsions were monitored based on the plasma concentration of phospholipids (PL) and triglycerides (TG), and the light scattering intensity (LSI) of plasma. Previously, we found that their time profiles after injection of the standard O/W lipid emulsion composed of soybean oil (SO) and egg yolk phosphatides (EYP) were similar and suggested that the oil particles with diameter of about 200 nm were entrapped by reticuloendothelial system (RES). Herein, in order to develop a delivery system to avoid the RES uptake by using the lipid emulsions, biological fate of lipid emulsions with oil particles of various sizes or those emulsified by surfactants with polyoxyethylene segments were subjected to the investigations. Lipid emulsions with oil particles of various sizes (about 150-550 nm) were prepared by altering EYP content. The oil particles were stable in plasma in vitro, but oil particle size decreased time-dependently after intravenous injection. Plasma clearance of oil particles depended on their initial size and was decreased by pretreatment with dextran sulfate 500 (DS500), a known RES suppressor. These results suggested that oil particles are still entrapped by RES, even for small-sized oil particles (about 150 nm). Lipid emulsion with small-sized oil particles was also prepared using medium chain triglycerides. The oil particles were stable in vitro, but the time profiles of plasma concentrations of PL and TG, and LSI of plasma were different, and oil particle size decreased time-dependently after intravenous injection. Plasma clearance of the oil particles also depended on their initial size and was decreased by DS500, suggesting that in vivo instability could be due to RES-mediated processes. Artificial surfactants with polyoxyethylene segments, HCO-60 (HCO60) and polysorbate 80 (PS80), were used for RES avoidance. HCO60 resulted in drastic reduction of the plasma clearance of the oil particles for both lipid emulsions composed of soybean oil and medium chain triglycerides. The time-dependent decrease of oil particle size after intravenous injection was marginal. In contrast, PS80 could not prolong the circulation time of the oil particles, and their size decreased time-dependently after intravenous injection.

O/W lipid emulsions for parenteral drug delivery. I. Pharmacokinetics of the oil particles and incorporated sudan II.

The potential usefulness of oil in water (O/W) lipid emulsions as parenteral drug delivery system for lipophilic drugs was examined in tumor-bearing rats. A model lipophilic drug, sudan II (PCoct = 226000), was formulated in five lipid emulsions consisting of soybean oil and various surfactants. Compared with HCO-60 micellar and plasma solutions of sudan II, the blood concentration of sudan II was markedly elevated by administration as a lipid emulsion. However, the distribution of sudan II to the liver, lungs, spleen, and adipose tissue was not altered, and that to the brain, heart, kidneys, muscle, and tumor was slightly decreased. To understand these results, pharmacokinetic analysis was performed using a newly derived compartmental model, and moreover, the organ distribution clearance was analyzed. It was suggested that the oil particles deliver the incorporated drug selectively to the liver, lungs, and spleen, and the speed of delivery could be surpressed by using HCO-60. However, in the case of sudan II, its rapid release from the oil particles after i.v. injection prevented a drastic alteration in the distribution of sudan II. The simulation studies suggested that a considerable decrease in the release rate or an increase in partition coefficient (experimentally more than 10(8) would be required for delivery.