Abuse-Resistant Modified/Controlled Release Narcotics/Opioid Analgesics
A major problem faced by the industry is the growing abuse and misuse of opioids by drug abusers, who attempt to extract the opioids from the drug products for the purposes of injection or otherwise achieve the immediate release of the large doses contained in extended release products. The proportion of narcotic/opioid analgesics abuse associated with emergency room admissions has more than tripled in ten years, from 6.8% in 1998 to 26.5% in 2008 (TEDS report, July 15, 2010). Narcotic/opioid analgesics abuse continues to increase as current products remain easy to abuse. In 2010, enough prescription painkillers were prescribed to medicate every American adult every 4 hours for one month (PBS 2013). The number of prescription medicine abusers in 2010 was 8.76 million, 5.1 million of whom abused painkillers (drugabuse.com 2013).
The market for opioid drugs, used to treat patients suffering from severe and chronic pain in the seven major markets (USA, Japan, and five European countries) was estimated to exceed $7.4 billion in 2010, dominated by oxycodone.
In 2014, the U.S. opioid drugs market was evaluated to be above $4.6 billion (IMS Health).
Flamel’s Trigger Lock™ platform utilizes Micropump®’s competitive advantages to allow the development of abuse-resistant modified/controlled release formulations of narcotics and other drugs susceptible to abuse:
- Micropump particles are extremely difficult to crush to extract the narcotic/opioid analgesics;
- Additional formulation modifications are made to prevent other less publicized methods of abusing controlled release technologies are available; and,
- Trigger Lock™ can provide products that are either bioequivalent to or have improved pharmacokinetics over marketed narcotic/opioid analgesics.
Trigger Lock™ is composed of
- Drug loaded Micropump® microparticles Sustained Release (SR) microparticleswhich are resistant to crushing
- Viscosifying ingredient(s)
To prevent abuse by injection after extraction in a small volume of solvent
- Quenching ingredient(s)
To prevent extraction in large volumes of liquid
These ingredients are all in the size range of 150-350 µm.
The high number of microparticles per dose (>20,000) prevents easy separation of these components.
Trigger Lock SR microparticles are resistant to crushingEach microparticle retains its polymer coating which is virtually impervious to further crushing and so the narcotic/opioid analgesics remains sequestered and unobtainable and the Trigger Lock™ powder exhibits identical release characteristics as the intact, overall tablet or capsule.
The FDA’s moves to restrict the prescribing of extended-release opioid analgesics should benefit abuse-resistant formulations, such as Trigger Lock™.
The FDA issued a “Draft Guidance for Abuse Deterrent Opioids” on January 9, 2013.
We believe that Trigger Lock™ has the potential to satisfy the FDA Draft Guidance for Abuse Deterrent Opioids:
- Laboratory-based in vitro manipulation and extraction studies (Category 1)
- Success with Trigger Lock™
- Pharmacokinetic studies (Category 2)
- Success with Trigger Lock™
- Clinical abuse potential studies (Category 3)
- To be performed prior marketing
- Analysis of post marketing data to assess the impact of an abuse-deterrent formulation on actual abuse in a community setting (Category 4)
- To be performed post marketing
Flamel presented in June 2015 results from two pilot pharmacokinetic studies, in both fasted and fed conditions, on Trigger-Lock hydromorphone, that clearly met the intention of the studies, i.e. to allow selecting the best formulation prototype, which satisfied most of the criteria necessary for proving bioequivalence of AUC to the comparator product Jurnista© (sold as Exalgo© in the United States), for further optimization and scale up with the aim to begin pivotal registration studies by mid-2016. In addition, the Company has generated substantial in vitro data comparing the abuse deterrence properties of Trigger Lock Hydromorphone (FT227) compared to other marketed abuse-deterrent opioid products. Further abuse deterrence data are being generated by an independent contract research organization and will be subject to further announcements. Flamel is planning to meet with the U.S. FDA before the end of 2015 to discuss the remainder of the development plan for FT227. The product is designed to be filed as a 505(b)(2) New Drug Application (NDA).