Anti-abuse formulations

Roberto Gabach – Director & Manager of New Projects

There are formulations created to reduce the possibility of drug abuse and misuse, making it difficult to administer it in conditions other than those approved.

The so-called “Abuse-Deterrent Formulations”, which will hereinafter appear as Anti-Abuse Formulations, are pharmaceutical compositions designed to reduce the possibility of manipulating a substance, eg opiates, making it difficult to administer it by a route or in conditions other than those approved: eg. nasal route (aspiration or inhalation), injectable route, by crushing the tablet, etc.

The most common form of substance abuse is simple oral overdose. However, the patient who abuses or is dependent on medications can try to intensify the effects by chewing, crushing, or grinding the tablet, dissolving it, or extracting the active ingredient with solvents to administer it by another route (nasal, injectable, etc).

The objective is to accelerate or intensify the expected effects by reducing the time in which the maximum concentration is reached or achieving a higher peak of drug levels in the blood.

To limit the possibility of abuse, drug developers use a variety of techniques to try to prevent misuse.

These include physical barriers (e.g. they prevent crushing the tablet or prevent it from dissolving when using gel-forming excipients that hinder the possibility of being injected or inhaled), prodrugs (minimize the maximum effects when the product is injected or inhaled because there is no metabolism of first hepatic step that quickly transforms the prodrug into active drug), aversive substances (capsaicin or sodium lauryl sulfate that causes irritation and pain if inhaled), the combination of agonists and antagonists (the antagonist is released if the tablet is chewed or crushed and injected).

Although abuse prevention strategies through special formulations offer therapeutic advantages, there are barriers to their approval (convincing the regulatory body of the real anti-abuse properties of the formulation) or prescription (more expensive products than non-anti-abuse ones).

In the USA there was a stimulus for the development of anti-abuse formulations as a consequence of dependence and overdoses with opiates (“opioid epidemic”). In that country, the number of fatal overdoses due to oral formulations of opioids (oxycodone, hydrocodone, hydromorphone, oxymorphone, etc.) has risen steadily since 2000.

In 2015, it was estimated that about 12 million people used opioid painkillers illicitly (without a prescription). Overdoses and deaths are mainly caused by the use of oral forms by alternative routes of administration such as intravenous, nasal aspiration, and in the form of cigarettes.

Over the years, the FDA has approved several products under the Abuse-Deterrent Formulation (ADF) label. Just to mention a few examples:

 

  • OxyContin ER: designed to prevent the tablet from being ground into a fine powder to be injected, or if this is achieved and dissolved in a solvent medium, a viscous gel is formed that prevents intravenous administration.
  • Embeda: they are capsules with pellets containing morphine surrounding the antagonist naltrexone that remains “sequestered” in the formulation. When the capsules are disintegrated, the naltrexone is released and prevents the oxycodone from acting (ie, it blocks the euphoria caused by the opiate). If the capsules are swallowed whole, naltrexone passes the gastrointestinal tract without being released.
  • Arymo ER: has a matrix of polyethylene oxide and morphine polymers surrounded by a hard shell that resists physical handling (e.g. crushing). Attempting to add a solvent forms a viscous gel that prevents intravenous administration.

 

Several oral formulations use the gel formation system to avoid forms of abuse in alternative to oral.

In the area of ​​transdermals, the company 4 P Therapeutics (now a subsidiary of Nutriband Inc) developed a formulation to prevent the abuse or misuse of opiates (abuse-deterrent fentanyl transdermal system).

In this transdermal system, the aversive agents are incorporated into the backing and are initially rapidly released and then prolonged when the patch is exposed to a dissolving medium.

They call the technology used by Nutriband AVERSA. This technology was first designed for a fentanyl patch, but the company’s goal is to extend it to buprenorphine and methylphenidate patches.

In January 2022, Nutriband received a patent grant notice on transdermal aversive technology in the USA. The company claims to have patents granted also in Europe, Japan, and Korea, in addition to Australia, Russia, and Mexico.

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