A Short Term Quality Control Tool for Biodegradable Microspheres

Abstract

Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C.

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

“…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.…”

A Review of In Vitro Drug Release Test Methods for Nano-Sized Dosage Forms

“…As with most dosage forms, product quality and performance may be verified through several in vivo and/or in vitro experiments [14]. Of these, drug release kinetics provides critical information about dosage form behavior and is a key parameter used to assess product safety and efficacy.…”

A reproducible accelerated in vitro release testing method for PLGA microspheres

“…Accelerated in vitro release testing based on elevated temperature has been successfully used as a fast quality control tool for PLGA based parenteral dosage forms (such as microspheres and implants) (D'Souza et al, 2014;Shen and Burgess, 2012a;Zolnik et al, 2006). Elevated temperature can accelerate PLGA polymer erosion (Zolnik et al, 2006), as well as enhance polymer mobility and thereby drug diffusion (Duda and Zielinski, 1996).…”

“…sample-andseparate, membrane dialysis, and continuous flow (USP apparatus 4)) have been used (D'Souza et al, 2014;Larsen et al, 2009;Zolnik et al, 2005). Ideally, an accelerated in vitro release method based on a compendial dissolution apparatus (e.g.…”