Microspheres based on inulin for the controlled release of serine protease inhibitors: preparation, characterization...

The pharmacological activity of serine protease inhibitors, potential drugs for the treatment of thrombosis, is often linked to the presence of amidine functions. With the aim of developing a suitable formulation for these compounds, inulin and inulin acetate associated or not with 1,12-dodecanedicarboxylic acid, were chosen to prepare microspheres. Using a coacervation method, these biocompatible polymers led to microspheres of about 0.5-5 microm. The encapsulation of a water-soluble model drug (E,E)-bis(amidinobenzylidene)cycloheptanone [(E,E)-BABCH] in these microspheres was studied. In this investigation, factorial designs were used to determine the joint influence of several variables (drug mass, speed and time of formulation stirring, centrifugation time) for an optimum encapsulation efficiency. Results revealed that encapsulation efficiency reached 65% whatever the nature of the biopolymer, by using a stirring time of 30 min, a high stirring speed and a centrifugation time of 15 min. (E,E)-BABCH release from microspheres was examined in an in vitro model. The profiles were characterized by three phases strongly dependent on the microspheres and the diacid association displayed a crucial role. With inulin and inulin acetate, the initial phase was a rapid 'drug burst'. Within the first 5 min, 58-62% of the drug were delivered. Microspheres of inulin acetate associated with 1,12-dodecanedicarboxylic acid, showed a slower release with only 32% of the drug delivered after 15 min. After a slow diffusion phase (33 h), an increasing rate until complete drug release was observed for 2.5 days.