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Abuse-deterrent opioid formulations generally fall into two categories: the first is based on a physiochemical abuse-deterrent approach and the second combines the opioid with an antagonist.
The United States is facing an opioid crisis. FDA has expressed concern about the growing epidemic of opioid abuse, dependence, and overdose, and part of its action plan includes a call to pharmaceutical manufacturers to develop opioid formulations with abuse-deterrent properties (1). As a result, there is increasing interest in the development of abuse-deterrent formulations as the technologies to prevent abuse among patients and recreational abusers continue to advance rapidly.
“Generally speaking, abuse-deterrent formulations should prevent drug abuse, but maintain clinical benefit and patient compliance,” says Michael DeHart, associate director, Pharmaceutical Development, Metrics Contract Services. “In other words, incorporating excipients to prevent drug abuse should not alter the bioavailability of the API or increase the tablet/capsule size dramatically.”
According to DeHart, one of the biggest challenges in developing an abuse-deterrent opioid formulation is that formulators are sometimes formulating from a reactive perspective. “A similar comparison can be made to how antivirus software developers must sometimes react to, or address, hackers who have already released a virus,” he says. “Drug abusers are highly resourceful and can generally ‘hack’ a formulation to get what they want.”
Current products on the market that contain abuse-deterrent labeling approved by FDA fall into two categories, highlights Angela Moore, scientist, Analytical Development, Alcami. One is based on a physiochemical abuse-deterrent approach and the other combines the opioid with an antagonist. “Physiochemical abuse-deterrent properties include products that are formulated to resist crushing, chewing, and physical manipulation. They contain excipients that will gel upon contact with solvents to make them difficult to inject intravenously,” she explains.
One of the more common excipients used to impart abuse-deterrent properties is polyethylene oxide (PEO), observes DeHart. “PEO can be cured or processed through hot-melt extrusion so that it cannot be crushed,” he says. “Grunenthal’s abuse-deterrent Intac Technology is based on this approach.” Tablets produced using Intac Technology have higher mechanical strength and are, therefore, resistant to crushing (2). An additional advantage is the low extractability of the active drug from the tablet in a wide range of solvents (2). “This low extractability is because PEO swells when exposed to various solvents,” DeHart says. The gelling of the polymer creates a viscous mass that is difficult to draw into a syringe, hence, raising the hurdles to drug abuse. DeHart notes that Purdue Pharma uses PEO in their reformulated OxyContin tablets.
“Opioid/antagonist products, on the other hand, contain the active opioid intended for therapeutic use as well as a sequestered antagonist, so that if the product is manipulated intentionally, it will release a chemical that will prevent the user from feeling the euphoric effects of the opioid,” Moore points out.
DeHart cites Pfizer’s Embeda as an example of an opioid formulation containing an antagonist. “In the case of Embeda, inactive naltrexone (i.e., the antagonist) is formulated with morphine sulfate in the capsules. If the capsules have been adulterated for potential abuse, the antagonist would become bioavailable and prevent any kind of abuse,” he says. “Opioid formulations may also include excipients such as sodium lauryl sulfate that can cause irritation when crushed and snorted.”
According to Moore, there are many considerations for manufacturers developing abuse-deterrent opioid formulations. “Most importantly, the product must be considered safe and effective, and it must adhere to all FDA manufacturing and testing guidelines,” she stresses. “From a chemistry and biologic perspective, the product must resist dose dumping and abuse, but still release the active ingredient when ingested as intended. From a commercial viewpoint, one of the key considerations is to develop a product that has a competitive advantage over those already on the market.” She explains that a company must differentiate its product in such a way that doctors will want to prescribe the new product over other available alternatives. She adds that insurance companies must also be convinced that the new product is worth paying more money for compared to cheaper products that do not contain abuse-deterrent formulation properties.
The current FDA guidelines (3) for determining the effectiveness of abuse-deterrence of a drug product involve four main studies, termed Category 1, 2, 3, and 4. “Category 1 testing involves laboratory manipulation and extraction studies,” says Moore. “In these studies, the product is evaluated and compared to currently marketed formulation(s) for the ability to defeat or compromise the abuse-deterrent properties. This testing is done in vitro and provides the physical characteristics of the product and its ability to resist crushing, grinding, melting, and to resist nasal abuse. Extraction studies provide information on the product’s ability to isolate the antagonist, or resist abuse by injection, or, in larger volumes, resist abuse by ingestion,” she explains.
“Category 2 testing involves pharmacokinetic studies in healthy humans. The product’s in-vivo properties are evaluated by comparing an intact formulation against the manipulated formulation through one or more routes of administration. Comparator products are also evaluated for comparison,” says Moore. She adds that Category 3 testing evaluates the clinical abuse potential of the product. “These are large, complicated in-vivo studies that are generally conducted with recreational drug users as test subjects. These test subjects are screened prior to the study to ensure that they are able to distinguish between the active drug and a placebo in a drug abuse setting. In these studies, the test subjects are provided the drug product being developed and suitable comparators. The drugs are administered through the route of abuse that is being studied (i.e., oral or intranasal) and the patients provide not only pharmacokinetic data, but also subjective data on the drug liking (how high they are) and if they would take the drug again,” she explains.
Moore highlights that Category 4 assessment is a post-approval study that determines if the product has resulted in meaningful reductions in abuse, misuse, or adverse clinical outcomes (addiction, overdose, and death). “These evaluations are conducted by the product manufacturer,” she says, pointing out that currently, there are no products on the market that qualify for the Category 4 label for abuse-deterrence.
“Recently, one of the more common tests that we have seen being used to evaluate the effectiveness of abuse-deterrent formulations is its syringeability,” DeHart notes. “Syringeability looks at how much opioid can be extracted from a tablet using heat, agitation, and in small volumes of water to see if it can be pulled through a syringe.”
According to DeHart, drug products that are susceptible to snorting should be evaluated for crushability and particle size distribution. He adds that tablets should also be evaluated to determine if dose dumping can be prevented. “Dose dumping typically occurs when painkillers are consumed with alcohol,” he explains. “It is, therefore, important to evaluate opioid release from drug products in dissolution media with various concentration of ethanol.”
While the pharmaceutical industry has a crucial role to play in developing opioid formulations that are more resistant to abuse and manipulation, the opioid crisis can only be tackled effectively if FDA, governments, policymakers, healthcare providers, patients, and their families to work together, as pointed out by FDA Commissioner, Scott Gottlieb (4).
1. FDA, “FDA Opioids Action Plan,”
accessed Dec. 13, 2017.
2. Grunenthal, Intac, www.intac.com, accessed Dec. 13, 2017.
3. FDA, Guidance for Industry: Abuse-Deterrent Opioids-Evaluation and Labeling (Rockville, MD, April 2015).
4. FDA, “Statement from FDA commissioner Scott Gottlieb, MD, on the Trump Administration’s Important Efforts to Address the Opioid Crisis,” Oct. 26, 2017.
Vol. 42, No. 1
When referring to this article, please cite it as A. Siew, “Tackling the Opioid Crisis with Abuse-Deterrent Formulations,” Pharmaceutical Technology 42 (1) 34–36 (2018).