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

Abstract

Sustained and total release of the sparingly water soluble compound, namely 1-[2-(4-fluorobenzoyl)aminoethyl]-4-(7-methoxynaphthyl) piperazine hydrochloride (FAM), from poly (DL-lactic acid) (PL A50) microparticles was previously 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 mixed with an additive. Such microparticles, where the additive was poly (ethylene glycol) (PEG), dimyristoylphosphatidylcholine (DMPC), or Poloxamer 6800, were administrated subcutaneously to rates either as depot or using a liquid vehicle. The variations of the plasma concentration vs time determined by high pressure liquid chromatography and fluorometric detection, were plotted for the various microparticle systems, blood being taken twice from 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 system. Kinetics experiments were performed over 24h and also for 7 days. It was found that, for the selected formulations, the release of the sparingly water soluble com pound 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 vitro investigation.