Manufacture, characterization, and elucidation of drug release mechanisms of etonogestrel implants based on ethylene vinyl acetate

Angela Ren; Ziyue Zhong; Yan Wang; Bin Qin; William Smith; Xiaoming Xu; Tony Listro; Feng Zhang

doi:10.1016/j.xphs.2024.08.015

Manufacture, characterization, and elucidation of drug release mechanisms of etonogestrel implants based on ethylene vinyl acetate

J Pharm Sci. 2024 Sep 3:S0022-3549(24)00315-0. doi: 10.1016/j.xphs.2024.08.015. Online ahead of print.

Authors

Angela Ren¹, Ziyue Zhong¹, Yan Wang², Bin Qin², William Smith³, Xiaoming Xu³, Tony Listro⁴, Feng Zhang¹

Affiliations

¹ The University of Texas at Austin, College of Pharmacy, Austin, TX, USA.
² U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA.
³ U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA.
⁴ Sever Pharma Solutions, Putnam, CT, USA.

PMID: 39236850
DOI: 10.1016/j.xphs.2024.08.015

Abstract

In this work, etonogestrel implants were manufactured using coextrusion. The purpose of the study was to correlate changes in microstructure and transport properties that occurred in etonogestrel implants to drug release mechanisms. The implants consisted of an EVA 28 (28% vinyl acetate) core containing dispersed and dissolved etonogestrel, and an EVA 15 (15% vinyl acetate) skin. The drug release was determined to be via diffusion at a controlled rate and governed by implant dimensions. In-vitro release revealed evidence of supersaturation in the implant core and skin, likely from the intense mechanical energy input during the twin-screw manufacturing process. Subsequently during storage under ambient conditions, supersaturation resulted in recrystallization of drug crystals, preferentially in the implant core. Etonogestrel solubility and diffusivity in EVA were determined by permeation experiments and used for release modeling. Drug release from the EVA skin layer deviated from the predicted values due to 1) formation of a drug depletion zone in the core and 2) presence of a stagnant media layer adjacent to the skin. Drug release from implant ends was significantly faster than predicted. Air-filled pores were observed in the implant core using microCT which likely contributed to the faster release from implant ends.

Keywords: Continuous processing; Controlled release; Diffusion; Extrusion; Injectable(s); Mathematical model(s); Polymeric drug delivery system(s).