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(lactideco-glycolide) microspheres. Peptide release was studied using a dialysis technique at 37°C and at elevated temperatures (50°C-60°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°C and 3 to 5 days at the elevated temperatures. In vitro release profiles at the elevated temperatures correlated well with release at 37°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, α, a scaling factor for the apparent rate constant. Complete release at 37°C was shortened from 30 days to 5 days at 50°C, 3.5 days at 55°C, 2.25 days at 60°C in PBS pH 7.4, and 3 days at 50°C in acetate buffer pH 4.0. Values for the model parameter β indicated that the shape of the release profiles at 55°C in PBS pH 7.4 (2.740) and 50°C in 0.1M acetate buffer pH 4.0 (2.711) were similar to that at 37°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 longterm 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.

Enhanced Degradation of Lactide-co-Glycolide Polymer with Basic Nucleophilic Drugs

“…As such, the degradation profiles at the acidic and alkaline conditions can be explained using the general acid-base catalysis where ester hydrolysis is enhanced by the presence of H+ or OH− ions in the aqueous media. Thus, the mechanism of PLGA hydrolysis in acidic or alkaline media is different from that observed in neutral media [31].…”

“…The elevated temperature experiments (accelerated tests) were later extrapolated for their use as a rapid evaluation technique for drug loaded polymeric dosage forms. The success of the devised technique, as noted by the interest in accelerated testing of biodegradable microspheres, is evidenced by a growing number of publications utilizing this methodology [31,35,36]. Additionally, accelerated tests have proven to be a useful tool to predict real-time in vitro behavior of biodegradable microspheres.…”

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

“…The release rate is often said to be diffusion-controlled initially and degradation/erosion controlled during the final stage of the release period (D'Souza et al, 2005;Fredenberg et al, 2011). The encapsulated drug may be released by more than one true release mechanism at once, and the dominating mechanism may vary with time (Wischke and Schwendeman, 2008;Fredenberg et al, 2011).…”

Preparation of Parenteral in situ Gel Formulation Based on smart PLGA polymer: Concepts to Decrease Initial Drug Burst and extend drug release

“…D'Souza et al reported that release from PLGA is initially diffusion-controlled followed by a degradation/erosion-controlled final stage [28]. Wang et al also illustrated a two-phase release profile for metoclopramide and its salt (monohydrochloride) from PLGA/benzyl benzoate solutions following injection into buffer: an early diffusion, followed by erosion [29].…”