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Published on: August 20, 2014
In vitro test methods for evaluating high molecular weight polyethylene oxide polymer induced hemolytic and
Dongjune Kim1, Rucha Natu2, Richard Malinauskas2
1US FDA, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Silver Spring, MD, United States of America; US FDA, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, United States of America.
Polyethylene oxide (PEO) in opioid formulations, intended to deter nasal abuse, has been linked to thrombotic microangiopathy (TMA) via intravenous injection. A new in vitro system is developed to assess PEO safety for injection routes.
Area of Science:
- Pharmacology
- Toxicology
- Materials Science
Background:
- Opioid abuse is a major public health concern, prompting regulatory action like the FDA's plan to increase abuse-deterrent formulations (ADFs).
- Polyethylene oxide (PEO) is a common excipient in ADFs, primarily designed to deter nasal insufflation.
- Shifting abuse patterns from nasal to intravenous (IV) routes have raised safety concerns regarding PEO-containing opioids, with reported cases resembling thrombotic thrombocytopenic purpura (TTP).
Purpose of the Study:
- To address the lack of in vitro assessment tools for evaluating the safety of PEO excipients when administered via intravenous injection.
- To investigate the mechanistic basis of high-molecular-weight (HMW) PEO-induced thrombotic microangiopathy (TMA).
- To develop a robust safety evaluation tool for PEO excipients in the context of unintended IV abuse.
Main Methods:
- Development of a dynamic in vitro test system simulating blood flow through a needle.
- Utilizing the developed system to assess the safety of PEO excipients under conditions mimicking IV drug abuse.
- Investigating the potential for PEO to induce TMA through mechanistic studies.
Main Results:
- Case reports indicate adverse effects similar to TTP following IV abuse of PEO-containing opioids.
- One opioid product containing PEO was removed from the market in 2017 due to increased IV abuse risks.
- A novel dynamic in vitro test system has been established for PEO safety evaluation.
Conclusions:
- Existing abuse-deterrent formulations may pose risks when abused via unintended routes, such as intravenous injection.
- There is a critical need for standardized in vitro methods to evaluate the safety of pharmaceutical excipients for parenteral administration.
- The developed dynamic in vitro system offers a promising tool for assessing PEO safety and understanding PEO-induced TMA mechanisms.
