The use of additives to modulate the release of a sparingly water soluble drug entrapped in PLA50 microparticles: in vivo investigation

Sustained and total release of the sparingly water soluble compound, namely 1-[2-(4-fluorobenzoyl)aminoethyl]-4-(7-methoxynaphthyl) piperazine hydroch loride (FAM), from poly (DL-lactic acid) (PLA50) microparticles was previou sly shown to be feasible if the particles are obtained by grinding a solid mixture composed of the polymer and a percolating array of the compound mix ed with an additive. Such microparticles, where the additive was poly (ethy lene glycol) (PEG), dimyristoylphosphatidylcholine (DMPC), or Poloxamer(R) 6800, were administrated subcutaneously to rates either as depot or using a liquid vehicle. The variations of the plasma concentration vs time determi ned by high pressure liquid chromatography and fluorometric detection, were plotted for the various microparticle systems, blood being taken twice fro m each animal and each measurement being triplicated. Data were analysed by non-compartmental analysis, in order to evaluate the elimination constant, the half-life, the area under the curve and the bioavailability for each s ystem. Kinetics experiments were performed over 24h and also for 7 days. It was found that, for the selected formulations, the release of the sparingl y water soluble compound depends on the dissolution rate in vivo and on the physicochemical characteristics of the additive, including solubility and micelle formation. Data correlated well with the results of previous in vit ro investigation.