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

Abstract

One of the major problems raised by the microencapsulation of drugs which are sparingly soluble in water is the difficulty to achieve a controlled and total release of the drug. It was previously shown that the microencapsulation of a model water insoluble drug, namely 1-[2-(4-fluorobenzoyl)aminoethyl]-4-(7-methoxynaphthyl) piperazine hydrochloride (FAMP) with a hydrophilic additive like low molar mass poly(ethylene glycol)s (PEG) can fulfil these requirements, provided all the drug+ additive matter is in contact with the surrounding liquid medium via open pores and percolating channels. In this paper, PEG was replaced by other additives, selected because of their potential ability to increase the solubility of FAMP in pH = 7.4 isosomolar phosphate buffer (PBS). The idea was that increasing the solubility locally in microparticles could allow the drug to be released, despite its poor solubility in aqueous media like body fluids, and be absorbed before recrystallization. The solubility in PBS of FAMP mixed with additive, in the form of solid dispersions, was determined for various additives, namely citric acid, dimyristoyl DL-alpha-phosphatidyl choline (DMPC), poloxamer copolymers of different compositions and poly(dodecyl L-lysine citramidate) (PLCAC12₁₀₀), 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 reference. It was found that DMPC, some poloxamers and the hydrophobized polyelectrolyte do increase the solubility of FAMP in PBS. Investigation was made of the release of FAMP from ground microparticles, whose loads were composed of FAMP combined with these solubilization-promoting additives. It was found that the release rate of FAMP from such systems can be increased and modulated to achieve an in vitro sustained release over a 20-30 day period and secure exhaustion of the particles at the end of this period.