Formulation development of a filter-sterilizable lipid emulsion for lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist.

Abstract

KW-3902 (a newly synthesized adenosine A1-receptor antagonist) has potent diuretic and renal protective activities. The objective of the present study was to develop an injectable formulation of KW-3902, that was water-insoluble and less than 1 microg/ml, and so lipid emulsion was selected as a favorable formulation. Changing the mixing ratio of oil to lecithin, the particle size of the lipid emulsion was controlled, and by adjusting the mixing ratio of oil/lecithin=1:1, the weight ratio, a lipid emulsion with a mean particle size of 130 nm was prepared. This small particle size makes this emulsion filter-sterilizable, which is a favorable feature for heat labile products. The stability of the KW-3902 lipid emulsion was assessed from the viewpoint of the electrostatic repulsion, and by including the oleic acid a stable lipid emulsion was developed, which was stable for at least 12 months at 10 and 25 degrees C and for 3 months at 40 degrees C. The feature of this small particle size emulsion was also characterized by comparing it with a conventional emulsion (oil/lecithin=1:0.12, the weight ratio, particle size is 220 nm). The release of KW-3902 from the oil particles was measured and the apparent permeability of KW-3902 was calculated from the equation according to Fick's theory. The apparent permeability, P, of KW-3902 was not affected by the particle size of the emulsion (1.78x10(-11) cm/s for the small emulsion and 1.76x10(-11)cm/s for the conventional emulsion). The distribution mode of KW-3902 in the lipid emulsion was also discussed by considering the findings of the permeability and solubility of KW-3902.