Formulation Development Forum: Abuse-deterrent combination drugs

Pfizer's (New York) $3.6-billion bid in mid-October to acquire the specialty pharmaceutical company King Pharmaceuticals (Bristol, TN) shows the increased strategic importance for large pharmaceutical companies to diversify their revenue streams through targeted acquisitions. For Pfizer, this move also signals its interest in building capabilities in formulation and drug delivery, including a specific class of therapeutics, abuse-resistant pain drugs.

In its Oct. 12, 2010 press release announcing its intention of acquiring King Pharmaceuticals, Pfizer noted that the market for pain relief and management is increasing with an estimated 320 million prescriptions written in the United States in 2009. "However, the widespread misuse and abuse of prescription pain treatments is a major public health issue and a growing economic burden for the entire industry," said Pfizer in the release. "King's leadership in new formulations of pain treatments designed to discourage common methods of misuse and abuse will provide Pfizer with multiple drug-delivery platforms while providing potential long-term upside."

King Pharmaceuticals has developed abuse-resistant versions of morphine and other opioid-based drugs. In August 2009, the company received US Food and Drug Administration approval for Embeda CII (morphine sulfate and naltrexone hydrochloride) extended-release tablet. Embeda is an example of an abuse-deterrent combination opioid drug or a combination drug developed with the intent to limit the abuse potential of the opioid component. One form way in which recreational users abuse opioid-based formulations is to crush or dissolve extended-release painkillers to obtain a particularly strong euphoric high. Embeda is a opioid formulation that seeks to address that problem. The drug contain pellets of an extended-release formulation of morphine sulfate surrounding an inner core of naltrexone hydrochloride. The formulation is designed to work such that if taken as directed, the morphine would relieve pain while the sequestered naltrexone would pass through the body with no intended clinical effect. Embeda is designed to be administered as intact capsules or intact pellets sprinkled over applesauce. Administered in this way, the absorption of naltrexone is negligible. If Embeda is crushed or chewed, however, the naltrexone would be released, mitigating the euphoric effect of the morphine.

King Pharmaceuticals has other abuse-deterrent combination opioid drugs under development. Remoxy is an extended-release oxycodone product, and Acurox is an immediate-release form of oxycodone . In July 2009, King Pharmaceuticals received a complete response letter from FDA for Remoxy The company said that at the time, that it believed that the rate-limiting step was the generation of six-moth stability data, and that no new clinical trials would be required. King Pharmaceuticals plans to resubmit a new drug application (NDA) for the drug by the end of this year, according to an Aug. 9, 2010 King Pharmaceuticals' press release.

Acurox is an orally administered, immediate-release tablet containing oxycodone hydrochloride as the active analgesic ingredient with a proposed indication for the relief of moderate-to-severe pain. The drug uses the specialty pharmaceutical company Acura Pharmaceuticals' (Palatine, IL) proprietary Aversion technology, which is based on using a composition of niacin and inactive ingredients that are designed to reduce the abuse of the drug substance. These ingredients generate a temporary, unpleasant effect if orally overconsumed, turn dissolved tablets into a thick gelatinous mixture, thereby making it difficult to draw the material into a syringe, or produce a mild burning sensation in the nostrils when crushed and snorted. Following an FDA advisory committee in April 2010 in which FDA questioned the effectiveness of niacin in the Acurox formulation, but not the abuse-limiting features of the product, the companies decided to submit an NDA for Acurox tablets (without niacin) in early 2011. Acurox, indicated to relieve moderate-to-severe pain, introduces limits and impediments to potential abuse by nasal snorting of crushed tablets and intravenous injection of dissolved tablets.

Acura Pharmaceuticals and King Pharmaceuticals also plan to develop and submit NDAs for two additional immediate-release opioid analgesic products using Acura's Aversion technology, according to a May 3, 2010 Acura Pharmaceuticals' press release. These include Vyacavert (hydrocodone bitartrate and acetaminophen) tablets and Acuracet (oxycodone hydrochloride and acetaminophen) tablets. These products are also formulations consisting of a mixture of active and inactive ingredients that are intended to relieve pain and introduce limits and impediments to nasal and intravenous abuse.

King Pharmaceuticals is also developing Oxycodone NT, a drug also designed to resist certain common methods of misuse and abuse. The company plans to begin Phase III trials later this year, according to the Aug. 9, 2010 release.