INJECTABLE POLYANHYDRIDE GRANULES PROVIDE CONTROLLED-RELEASE OF WATER-SOLUBLE DRUGS WITH A REDUCED INITIAL BURST

A method for preparing polyanhydride granules of an injectable size wa s developed. The resulting granules permitted a nearly constant releas e of low-molecular-weight, water-soluble drugs without an initial burs t. The polyanhydrides used were poly(fatty acid dimer), poly(sebacic a cid), and their copolymers. The dyes acid orange 63 and p-nitroaniline were used as model compounds for drugs. Polymer degradation and drug release for disks and variously sized granules of copolymers containin g drugs, prepared by a water-in-oil (W/O) emulsion method, were compar ed with those for devices prepared by the usual compression method. In the W/O emulsion method, a mixture of aqueous drug solution and polym er-chloroform solution was emulsified by probe sonication to prepare a very fine W/O emusion. The powder obtained by freeze-drying of the W/ O emulsion was pressed into circular disks. In the compression method, the drug was mechanically mixed with the polymer, and the mixture was compressed into circular disks. The resulting disks were ground to pr epare granules of different sizes. The granules encapsulated more than 95% of the drug, irrespective of the preparation method. Both methods were effective in preparing polymer disks capable of controlled drug release without any initial burst. However, as the granule size decrea sed to an injectable size (diameter, <150 mu m), a large difference in the drug release profile was observed between the two preparation met hods. The injectable granules obtained by the W/O emulsion method show ed nearly constant drug release without any large initial burst, in co ntrast to those prepared by the compression method, irrespective of th e drug type. Degradation studies of the granules demonstrated no diffe rence in the degradation profile of the granule matrix itself between the two methods. Light microscopic observations of polymer disk prepar ed by the compression method indicated a nonuniform distribution of dy e islands throughout the matrix. In contrast, a highly homogeneous mix ing of dye and polymer was achieved for devices prepared by the W/O em ulsion method. It is therefore possible that this highly uniform distr ibution of drug throughout the polymer matrix leads to a reduced initi al burst in drug release from the injectable granules obtained by the W/O emulsion method.