SC I E N C E & T EC H N O LO GY
PROBLEM PILL
addictive properties and potential for abuse. They agreed to pay $634.5 million in fines. The reformulated version of OxyContin that Purdue presented to the FDA panel last month has features designed to deter tampering with the tablets. According to Purdue, the pills’ formulation makes them more resistant to mechanical forces, such as crushing and chewing, as well as extraction. In the presence of water, an unnamed excipient forms a goo that’s hard to draw up into a syringe.
N EWSCO M
Abuse of prescription opioids such as OxyContin, pictured here being seized as evidence, is on the rise.
FORMULATIONS FOR FIGHTING ABUSE Opioid makers aim to THWART MISUSE with excipients, additives, and antagonists BETHANY HALFORD, C&EN WASHINGTON
pain relievers for nonmedical purposes, acIN 1898, chemists at Bayer believed they cording to the most recent National Survey had a wonder drug on their hands. Their on Drug Use & Health. newest pain reliever and cough remedy, a In light of the multi-billion-dollar diacetylated form of morphine, was more market for pain relievers, pharmaceutical potent than its parent opioid with HO makers have been racing to create abuseone-tenth of its toxic CH3 effects. And unlike mordeterrent formulations of opioids, an effort N that’s been spurred on by the Food & Drug phine, this compound O Administration. Last month, a panel of the wasn’t habit-forming, or so agency’s scientific advisers met to evaluate H proclaimed one report in the one such drug, Purdue Pharma’s reformuBoston Medical & Surgical JourHO lated version of OxyContin. nal. The wonder drug’s reputaIntroduced in 1995, OxyContin is a tion so impressed the members Morphine controlled-release formulation of oxyof the St. James Society codone that provides 12 that the U.S. philanthropic organi- CH3O CH3 hours of pain relief. Pain zation began a campaign to mail free N management specialists samples of the stuff to morphine addicts O hailed OxyContin as a breakwho were trying to kick the habit. That wonder drug was heroin. It OH through, and by 2001 it was the most frequently prescribed didn’t take long to discover that heroin O brand-name narcotic for treattablets could be crushed and snorted Oxycodone ing moderate-to-severe pain in or dissolved and injected to deliver a the U.S., bringing in more than tremendous high. $1 billion in annual sales. A century later, opioid makers still strugAt the same time, reports were surfacgle with the compounds’ potential for abuse. ing about the drug’s potential for abuse. These drugs bring relief to millions of peoCrushing, chewing, or dissolving the tablets ple who suffer from chronic pain—one in 10 destroys the controlled-release feature, American adults have experienced pain that delivering the entire dose of oxycodone at lasted for more than a year, according to the once and a heroin-like high along with it. National Center for Health Statistics. But Last year, Purdue and three of its executives the euphoria that opioids induce also makes pleaded guilty to misleading regulators, them susceptible to abuse. In 2006, more doctors, and patients about OxyContin’s than 12 million Americans used prescription W W W.C E N - O N L I N E .O RG
40
J U N E 9, 20 0 8
FDA’S EXPERT advisers, however, were apprehensive about the new formulation, citing “poor scientific rigor” in Purdue’s data. They weren’t convinced that the new formulation would be effective in the real world, and they felt that indicating the tablets were somehow tamper-resistant might give doctors and patients the impression that the drugs aren’t abusable or don’t carry risks of addiction or overdose. “The first thing that one needs to realize is that the problem of prescription opioid abuse takes a number of very different forms, each of which would look different from the point of view of a formulation chemist,” says Nathaniel Katz, director of the Program on Opioid Risk Management at Tufts Health Care Institute, who frequently consults for pharmaceutical companies developing abuse-deterrent formulations of opioids. “Some pieces of these problems may be addressable with formulation and some may not.” Katz points out that there’s never been a systematic study to determine the causes behind fatal overdoses of prescription opioids. Although tampering with tablets and then snorting or injecting them may be behind some deaths, he says, it’s also likely that many overdoses occur when people who are not tolerant to opioids swallow large doses of the drugs. Tamper-resistant pills won’t solve that problem. Regardless, Katz says, prescription opioid abuse “is an enormous public health problem,” and abuse-deterrent drugs have the potential to help curb it. Despite Purdue’s setback with the FDA advisory panel, Katz believes the agency is still eager to bring effective abuse-deterrent formulations to the market. That’s good news for the handful of companies that are pursuing such drugs.
antagonist used to treat opioid dependence. for Embeda in February but withdrew the “We are working hard to come up with a A porous coating encapsulates the application in April. The firm says it plans to new kind of medicine that addresses this oxycodone and a nonporous polymer resubmit the NDA shortly and is hoping to very important public health concern,” covers the naltrexone. The porous coatlaunch Embeda in the first quarter of 2009. says Eric Carter, chief science officer at ing dissolves away in the digestive tract, FDA says it will consider letting drugKing Pharmaceuticals. “Opioids are a good slowly releasing the oxycodone. Digestive makers add language to the labels of medicine when used appropriately.” juices can’t get through nonporous coating these pain relievers that highlights their In partnership with Pain Therapeutics, around the naltrexone, so it never enters abuse-deterrent features, but long-term King has been developing Remoxy, its own the system if taken orally. epidemiological studies are necessary long-acting formulation of oxycodone to determine if any of these drugs truly that’s physically resistant to crushing and curb abuse. “There is no such thing as dissolving. Remoxy is a sustained-release CRUSHING or chewing the beads releases an absolute abuse-proof formulation,” gel cap; its oxycodone is suspended in a the naltrexone, which in turn blocks any warns Stuart Apfel, chief scientific officer viscous matrix based on sucrose acetate euphoric effects from the oxycodone. In at Elite. “The goal of our formulation and isobutyrate, an emulsifier used in proa study, recreational drug users reported everybody else’s formulations is to make cessed foods. that consuming crushed ELI-216 gave them it so much more difficult to abuse that the Crushing Remoxy yields only HO virtually no high. Elite is preparrecreational user will find it inconvenient a thick gel and won’t disrupt ing to take the drug into N enough not to abuse.” the chemical matrix that releases Phase III clinical trials later O “Formulation is just a part of making the drug slowly, Carter says. King this year. opioids safer,” Tufts’s Katz points out. hopes to file a New Drug ApplicaAlpharma has used a similar tactic OH Doctors also need to prescribe opioids tion (NDA) for Remoxy within the O with its long-acting morphine forsafely, he says, by screening for patients next few months. mulation called Embeda. Embeda and households at risk for drug abuse. UltiKing is also working on a shortNaltrexone has a pellet core of naltrexone that mately, Katz says, “the only thing that’s goacting, abuse-deterrent formulation of passes through the gastrointestinal ing to solve the prescription opioid abuse oxycodone called Acurox. Carter notes that tract intact. Crushing, chewing, or dissolvproblem is to develop analgesics that are while abuse of long-acting drugs, such as ing the pill releases the euphoria-curbing not addictive.” ■ OxyContin, have gotten a lot of attention in naltrexone. Alpharma submitted an NDA the press, the larger public health concern is with abuse of short-acting formulations, due to the sheer number of prescriptions CONTINUING TO REVOLUTIONIZE dPEG TM that are written for these medications. Acurox, which King is developing with Acura Pharmaceuticals, contains a subtherapeutic amount of niacin. Take the medicine as prescribed and you’ll never notice the niacin, but in high doses the NEW CROSSLINKERS!! THE OLD SPDP AND MBS MADE NEW additive brings on unpleasant sensations ™ AND USEFUL WITH dPEG s of flushing, itching, redness, and gastrointestinal discomfort. “What this technology attempts to do is discourage overuse of opioids,” Carter explains. “You can’t just keep popping these tablets because the niacin makes you uncomfortable.” Acurox is also formulated to irritate SEE OUR WEBSITE WITH A NEW FRESH LOOK AND FEATURES, AS WELL AS nasal passages if snorted, Carter says. And OUR EXTENSIVE LINES OF SYNTHETICALLY PRODUCED SINGLE it contains an excipient that creates a geMONODISPERSED dPEG™ OPTIONS IN MODIFICATION, latinous mass if it comes in contact with water, making it difficult to inject. King CLICK REAGENTS, LABELING AND PEPTIDE SYNTHESIS anticipates filing an NDA for Acurox by the end of the year. Scientists at Elite Pharmaceuticals are taking a different approach with their long-acting pain killer, ELI-216. A 24-hour extended-release formulation, ELI-216 comes as a capsule filled with tiny white beads. “Physically the beads look identical,” explains Chris Dick, FAX YOUR ORDERS TO 614 760-9781 OR E-MAIL
[email protected] Elite’s executive vice president of corpoWWW.QUANTABIODESIGN.COM rate development, but some contain oxycodone and some contain naltrexone—an W W W.C E N - O N L I N E .O RG
41
J U N E 9, 20 0 8
R EQU EST M O R E AT A D I N FO N OW.O RG
BIOCONJUGATION
