In vitro delivery of a sparingly water soluble compound from PLA50 microparticles

The administration of a sparingly soluble drug is always problematic, espec ially when the drug has to be released from the degradable matrix of a poly meric drug delivery system. Attempts were made to achieve the complete rele ase of 1-[2-(fluorobenzoyl) aminoethyl]-4-(7-methoxynaphtyl)piperazine (FAM P), a potential anxiolytic and antidepressor hydrophobic compound, from rac emic poly(lactic acid) (PLA(50))-based microparticles, 100% release was req uired at a low rate in order to allow monthly repeated S.C. or I.M. injecti ons of this potent compound. FAMP-polymer combinations were made in the for m of microspheres by the solvent evaporation technique. Release profiles we re investigated under dynamic conditions by using a constant how rate of pH 7.4 0.15 M phosphate buffer, used as a model of body fluids. Under these c onditions, none of the microsphere compositions led to total release within a month, even when hydrophilic excipients, namely fructose and PEG were ad ded. PLA(50)-FAMP microparticles with compositions and sizes similar to tho se of the microspheres, were then made by direct blending in dichloromethan e, evaporation of the solvent, grinding and sieving. These formulations als o failed in providing total drug release within 30 days, even at a high dru g load. FAMP/PLA(50)/water-soluble additive, ternary grounded particles wer e finally prepared with fructose, PLA(50) oligomers or poly(ethylene glycol ) (PEG) as the additive. Only PLA(50) grounded particles with percolating F AMP-PEG microdomains allowed 100% release of FAMP over a 30 day period, at a quasi constant rate which depended primarily on solubility and channellin g provided the flow was slow enough. Data are discussed in terms of the acc essibility of the entrapped drug to the aqueous medium.