Marked enhancement in antithrombotic activity of isocarbacyclin following its incorporation into lipid microspheres.

Isocarbacyclin, (+)-9(O)-methano-delta 6 (9 alpha)-PGI1 (TEI 7165) and its methyl ester (TEI 9090) were incorporated in lipid microspheres (LM) with a diameter of 0.2 micron, in an attempt to increase their efficacy, possibly by way of targeting the drugs to the site of vascular damage. When the two LM-preparations were incubated in 2% bovine serum albumin solution, it was shown that TEI 7165 was released rapidly from LM, while the release of TEI 9090 was slow. Thus, TEI 9090 in LM, injected intravenously, may not be released largely in plasma before the distribution of LM to the target sites. The antithrombotic activity of the LM preparation of TEI 9090 was then compared with that of TEI 9090 as such in the hamster cheek pouch model. It was found that TEI 9090 incorporated in LM was more than 500 times more potent as an inhibitor of ADP-induced thrombus growth. These data suggest that prostacyclin analogues incorporated in LM may be used safely as potent antithrombotic agents in the clinical application.