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

One of the major problems raised by the microencapsulation of drugs which a re sparingly soluble in water is the difficulty to achieve a controlled and total release of the drug. It was previously shown that the microencapsula tion of a model water insoluble drug, namely 1-[2- (4-fluorobenzoyl) aminoe thyl]-4-(7-methoxy-naphthyl) piperazine hydrochloride (FAMP) with a hydroph ilic additive like low molar mass poly(ethylene glycol)s (PEG) can fulfil t hese requirements, provided all the drug + additive matter is in contact wi th the surrounding liquid medium via open pores and percolating channels. I n this paper, PEG was replaced by other additives, selected because of thei r potential ability to increase the solubility of FAMP in pH = 7.4 isosomol ar phosphate buffer (PBS). The idea was that increasing the solubility loca lly in microparticles could allow the drug to be released, despite its poor solubility in aqueous media like body fluids, and be absorbed before recry stallization. The solubility in PBS of FAMP mixed with additive, in the for m of solid dispersions, was determined for various additives, namely citric acid, dimyristoyl DL-alpha-phosphatidyl choline (DMPC), poloxamer(R) copol ymers of different compositions and poly(dodecyl L-lysine citramidate) (PLC AC12(100)), an aggregate-forming hydrophilic polyelectrolyte containing 100 % hydrophobizing ester groups which can accommodate lipophilic compounds in hydrophobic pockets present in the aggregates. PEG was taken as a referenc e. It was found that DMPC, some poloxamers(R) and the hydrophobized polyele ctrolyte do increase the solubility of FAMP in PBS. Investigation was made of the release of FAMP from ground microparticles, whose loads were compose d of FAMP combined with these solubilization-promoting additives. It was fo und that the release rate of FAMP from such systems can be increased and mo dulated to achieve an in vitro sustained release over a 20-30 day period an d secure exhaustion of the particles at the end of this period.