An In Vitro Thrombolysis Study Using a Mixture of Fast-Acting and Slower Release Microspheres

Abstract

Purpose: To test the hypothesis that a mixture combining fast and slower release rate microspheres can restore blood flow rapidly and prevent formation of another blockage in thrombolysis. Methods: We used polyethylene glycol (PEG) microspheres which provide the release of the encapsulated streptokinase (SK) on the scale of minutes, and Eudragit FS30D (Eud), a polymethacrylate polymer, for development of delayed release microspheres which were desirable to prevent a putative second thrombus. Eud microspheres were coated with chitosan (CS) to further extend half-life. Experiments included the development, characterization of Eud/SK and CS-Eud/SK microspheres, and in vitro thrombolytic studies of the mixtures of PEG/SK and Eud /SK microspheres and of PEG/SK and CS-Eud/SK microspheres. Results: CS-Eud/SK microspheres have slightly lower encapsulation efficiency, reduced activity of SK, and a much slower release of SK when compared with microspheres of Eud/SK microspheres. Counter-intuitively, slower release leads to faster thrombolysis after reocclusion as a result of greater retention of agent and the mechanism of distributed intraclot thrombolysis. Conclusions: A mixture of PEG/SK and CS-Eud/SK microspheres could break up the blood clot rapidly while providing clot-lytic efficacy in prevention of a second blockage up to 4 h.