A novel stable supersaturated submicron lipid emulsion of tirilazad.

This paper describes a novel supersaturated submicron lipid emulsion for parenteral drug delivery. Tirilazad was used as an amphiphilic model drug for the preparation and characterization of the supersaturated emulsions with concentrations more than two times higher than the drug solubility in the emulsion. Analysis of particle size distribution using photon correlation spectroscopy indicated that the mean particle diameters of the supersaturated 10 and 20% lipid emulsions of tirilazad were approximately 210 and 240 nm, respectively, and that the mean particle size and size distribution of the supersaturated tirilazad emulsions were not different from those of the non-supersaturated tirilazad emulsions. The apparent viscosity of the supersaturated tirilazad emulsions, as measured by continuous rheometry, was similar to that of the non-supersaturated tirilazad emulsions. However, the zeta potential of the supersaturated tirilazad emulsions, as determined by the electrophoretic light-scattering technique, was found to be dependent on drug load and was lower than that of the non-supersaturated tirilazad emulsion. Fractionation by ultracentrifugation showed that at low drug loads, the amount of drug associated with the emulsion particles and the infranatant fraction appeared to increase linearly with increasing concentration of the drug. By contrast, the amount of drug associated with the emulsion particles increased rapidly, whereas the amount of drug associated with the infranatant fraction remained constant for emulsions with a high drug load. These results suggest that the excess drug in the supersaturated emulsions is largely associated with the lipid phase. Accelerated stability studies under stress conditions (i.e., autoclaving and shaking) and long-term storage stability tests demonstrated that the supersaturated tirilazad emulsions had excellent physical stability over the study period of 16 months.

Venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats following intravenous administration of a novel supersaturated submicron lipid emulsion.

PURPOSE: To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. METHODS: Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography. RESULTS: Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p > 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower V(ss), (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p < 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. CONCLUSIONS: Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.