Characterization of attributes and in vitro performance of exenatide-loaded PLGA long-acting release microspheres

Tinghui Li, Aishwarya Chandrashekar, Avital Beig, Jennifer Walker, Justin K.Y. Hong, Alexander Benet, Jukyung Kang, Rose Ackermann, Yan Wang, Bin Qin, Anna S. Schwendeman, Steven P. Schwendeman

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Bydureon® (Bdn) is a once-weekly injectable long-acting release (LAR) product for adults with type 2 diabetes based on PLGA microspheres encapsulating the glucagon like peptide (GLP-1) analog, exenatide. Despite its widespread use in type 2 diabetes treatment, little information has been published concerning the physical-chemical aspects and exenatide stability in this product. Here, we developed and validated methods to evaluate attributes and performance of Bdn such as particle size/size distribution and residual levels of moisture and organic solvent(s). The reverse engineering of the exenatide LAR was also performed to identify and quantify principal components in the product. Stability-indicating UPLC and LC-MS methods were applied to characterize exenatide degradation (such as oxidation, deamidation and acylation products) during in vitro release evaluation. The 55-μm volume-median Bdn microspheres slowly released the exenatide in vitro over two months with a very low initial burst release to avoid unwanted side effects. Residual organic solvent levels (methylene chloride, ethanol, heptane, and silicon oil) also met the USP criteria. Peptide acylation was the most prominent peptide reaction during both encapsulation and in vitro release, and the acylated peptide steadily increased during release relative to parent exenatide, becoming the most abundant peptide species extracted from the microspheres at later release stages. The presence of peptide impurities during the release period, which are not extractable in the polymer and likely insoluble in water, might be one potential cause for immunogenicity. Further evaluation will be needed to confirm this hypothesis. Release of peptide was minimal over the first 2 weeks before the microspheres steadily released peptide for more than 28 days. The rigorous technical approach discussed in this paper may provide critical information for both companies and the FDA for developing generic exenatide-PLGA formulations and other important PLGA microsphere products.

Original languageEnglish
Pages (from-to)401-409
Number of pages9
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume158
DOIs
StatePublished - 1 Jan 2021
Externally publishedYes

Keywords

  • Bydureon Bcise®
  • Exenatide
  • Exenatide sustained-release
  • PLGA microspheres
  • Reverse engineering

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science

Fingerprint

Dive into the research topics of 'Characterization of attributes and in vitro performance of exenatide-loaded PLGA long-acting release microspheres'. Together they form a unique fingerprint.

Cite this