A model-dependent approach to correlate accelerated with real-time release from biodegradable microspheres

Abstract

The purpose of this study was to determine the feasibility of applying accelerated in vitro release testing to correlate or predict long-term in vitro release of leuprolide poly(lactide-co-glycolide) microspheres. Peptide release was studied using a dialysis technique at 37 degrees C and at elevated temperatures (50 degrees C-60 degrees C) in 0.1M phosphate buffered saline (PBS) pH 7.4 and 0.1M acetate buffer pH 4.0. The data were analyzed using a modification of the Weibull equation. Peptide release was temperature dependent and complete within 30 days at 37 degrees C and 3 to 5 days at the elevated temperatures. In vitro release profiles at the elevated temperatures correlated well with release at 37 degrees C. The shapes of the release profiles at all temperatures were similar. Using the modified Weibull equation, an increase in temperature was characterized by an increase in the model parameter, alpha, a scaling factor for the apparent rate constant. Complete release at 37 degrees C was shortened from approximately 30 days to 5 days at 50 degrees C, 3.5 days at 55 degrees C, 2.25 days at 60 degrees C in PBS pH 7.4, and 3 days at 50 degrees C in acetate buffer pH 4.0. Values for the model parameter beta indicated that the shape of the release profiles at 55 degrees C in PBS pH 7.4 (2.740) and 50 degrees C in 0.1M acetate buffer pH 4.0 (2.711) were similar to that at 37 degrees C (2.677). The E(a) for hydration and erosion were determined to be 42.3 and 19.4 kcal/mol, respectively. Polymer degradation was also temperature dependent and had an E(a) of 31.6 kcal/mol. Short-term in vitro release studies offer the possibility of correlation with long-term release, thereby reducing the time and expense associated with long-term studies. Accelerated release methodology could be useful in the prediction of long-term release from extended release microsphere dosage forms and may serve as a quality control tool for the release of clinical or commercial batches.