Stabilization of vinca alkaloids encapsulated in poly(lactide-co-glycolide) microspheres

Purpose. The purpose of this study was to stabilize the vinca alkaloids, vi ncristine sulfate (VCR) and vinblastine sulfate (VBL), in poly(lactide-co-g lycolide) (PLGA) microspheres and to release the drugs in a sustained manne r for more than a month. Methods. An oil-in-oil emulsion-solvent extraction method was used to encap sulate VCR and VBL in PLGA50/50 microspheres. Stability and release kinetic s of the drugs during the incubation at 37 degrees C in PBS/Tween 80 were a ssessed by HPLC. Degradation products were identified with HPLC-MS. Results. VCR and VBL were encapsulated in PLGA microspheres unchanged. Duri ng the microsphere incubation, however, VCR degraded inside the particles w ith a t(1/2) similar to 7.5 days. The degradation product was identified by LC-MS as the deformyl derivative, commonly formed at acidic pH. VBL, which differs only by a stable methyl group in place of the N-formyl group in VC R, was completely stable in the PLGA microclimate. The neutralization of ac idic PLGA microclimate by addition of 3-10% Mg(OH)(2) completely inhibited deformylation of VCR during release, but introduced a new degradation produ ct formed under the more alkaline conditions used during the preparation. T he substitution of Mg(OH)(2) with a weaker base, ZnCO3, inhibited the forma tion of both degradation products resulting in VCR stabilization of >92% fo r 4 weeks. The optimal formulations of VCR (containing ZnCO3) and VBL (no a dditives) slowly and continuously released stable drugs for over a month. Conclusions. VCR and VBL were successfully stabilized and released in a sus tained manner from PLGA microspheres. Co-encapsulation of ZnCO3 stabilizes VCR against acid-catalyzed degradation during release from the polymer and minimizes VCR decomposition during encapsulation.