Remoxy with Oradur Technology Opioid with an Abuse Resistant Formulation

Abuse of controlled-release formulations of oxycodone and other prescription opioids is a large, fast-growing problem in the US. Simply crushing and dissolving these formulations can yield the full 12 h dose to produce an immediate, large spike in opiate blood levels and a powerful morphine-like high, as well as the potential for respiratory depression and death. In the US in 2002, oxycodone abuse resulted in over 22,000 Emergency Room visits (nearly 20% of ER visits due to abuse of narcotic analgesics), according to the Drug Abuse Warning Network (DAWN), a division of the Substance Abuse and Mental Health Services Administration (SAMHSA). This dramatic increase has coincided with the 1996 introduction and marketing of OxyContin® (Fig. IV-33). Between 2002 and 2003, the number of people over 12 years old reporting abuse of OxyContin® increased from 1.9 million iTypeunspec. ■ IR Type CR Type

55,000 20,000 15,000 10,000 5.DOO

—i—^—i—^—i—^^ i ^^ i ^^ i ^—i—^—i- ^^

1994 1995 1996 1997 1998 1999 2000 2001 2002

IR »immediate release CR = condoled release

Figure IV-33. Emergency room visits involving oxycodone abuse. Adapted from DAWN

to 2.8 million, according to the National Survey on Drug Use and Health. Most alarmingly, in a 2005 survey conducted by the National Institute on Drug Abuse (NIDA), 5.5% of 12th-graders reported abusing OxyContin®.

Contrary to oxycodone slow release, the opioid is embedded in a sustained released oral gel-cap which provides unique characteristics. This is based on the ORADUR technology, which can take the form of an easy to swallow gelatin capsule that uses a high-viscosity base component, SABER™. This provides sustained release of active ingredients for a period of from 12 to 24 h (Durect Corporation Cupertino, Pain Therapeutics South San Francisco, and King Pharmaceuticals). Oral dosage forms based on the ORADUR gel-cap may also have the added benefit of being less prone to abuse than other controlled release dosage forms on the market today. Pain Therapeutics' Remoxy™ is an abuse-resistant version of long-acting oxycodone and has a sticky, high-viscosity capsule formulation (Fig. IV-34). This makes it difficult for drug abusers to inject or snort Remoxy™. Being a novel long-acting oxycodone formulation it is primarily designed to deter oxycodone abuse. In vitro tests show that Remoxy™ cannot be fragmented by forceful crushing, even after freezing at - 80 °C, and that its oxycodone content cannot be extracted by dissolution in alcohol or other common beverages. Ingesting OxyContin® after crushing and dissolving in water or alcohol produced plasma oxycodone levels even slightly higher than ingestion of an equivalent strength immediate release oxycodone tablet. In contrast, oxycodone plasma concentrations following similar treatment of Remoxy™ remained far below those of the comparable immediate release agent.

Figure IV-34. The soft-gel tablet Remoxy™ which has a sticky, high-viscosity mass that resists injection or snorting. Freezing, crushing or submerging Remoxy® in high-proof alcohol for hours at a time releases just a fraction of oxycodone compared to Oxycontin® at time points when abusers presumably expect to get high

Figure IV-34. The soft-gel tablet Remoxy™ which has a sticky, high-viscosity mass that resists injection or snorting. Freezing, crushing or submerging Remoxy® in high-proof alcohol for hours at a time releases just a fraction of oxycodone compared to Oxycontin® at time points when abusers presumably expect to get high

The FDA has not yet evaluated the merits, safety or efficacy of Remoxy® and the company has just finished a large, pivotal Phase III registration study that can support a New Drug Application under an FDA filing strategy. However, Remoxy™ received a Special Protocol Assessment (SPA) from the FDA in February 2006, which specifies the Phase III trial objective, design, clinical endpoints, and analyses needed to support regulatory approval. Under the terms of the SPA, just one pivotal trial is required to file a New Drug Application. The randomized, double-blinded, placebo-controlled, multicenter trial will enroll 400 patients with moderate-to-severe osteoarthritic pain in the US. Patients will be randomized to either Remoxy™ (10 mg daily) or placebo for 12 weeks. After Remoxy™ receives marketing approval, the company Pain Therapeutics has a strategic alliance with King Pharmaceuticals to develop and market Remoxy™ and other abuse-resistant opioids.

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