Modified dextran, heparin-based triggered release microspheres for cardiovascular delivery of therapeutic drugs using protamine as a stimulus.

In this study, we describe the synthesis of an amine-modified acetalated dextran polymer, which is combined with heparin (HP) as the basis for a novel controlled release system. Dextran-amine (DEXAM) conjugates, synthesised using reductive amination, were incorporated into DEXAM/HP microspheres. HP binds to positively charged ammonium ions of the DEXAM conjugates, contributing to the structural integrity of the microspheres. Crystal violet (CV) was encapsulated inside DEXAM/HP microspheres as a model drug to test the system. Protamine with a high affinity for HP functioned as a trigger to release CV. DEXAM/HP microspheres were characterised by particle size, encapsulation efficiency, scanning electron microscope images, and in vitro release profile. Release of CV from microspheres varied with primary amine content of DEXAM conjugates, amount of HP, and concentration of protamine added. The system is considered for controlled delivery of agents without the necessity of chemical modification.

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

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.

Biphasic release of protein from polyethylene glycol and polyethylene glycol/modified dextran microspheres.

Dextrans show great promise for delivery of therapeutic agents. Dextran acetates (DAs) were synthesized with increasing degrees of substitution (DA1 < DA2 < DA3) by the reaction of the polysaccharide dextran (70 kDa) with acetic anhydride. A series of polyethylene glycol (PEG)/DA microspheres were prepared and tested with bovine serum albumin (BSA) functioning as a model protein. Particle size (0.74-0.85 µm) and encapsulation efficiency (56-70%) increased with the degree of substitution along with a slower release rate of protein from PEG/DA microspheres. Time to release 90% of protein rose from 31 to 118 min. Percentage of BSA released from PEG and PEG/DA3 microspheres with time (min) was modeled mathematically [Y(PEG) = 100(1 - e(-0.12t)); Y(PEG/DA3) = 100(1 - e(-0.024t))] to predict cumulative delivery from mixtures in vitro over a period of hours when constrained to a target level at 30 min. The system is examined for potential application in thrombolytic therapy.