The recently concluded hit AMC series Breaking Bad certainly brought the problem of methamphetamine abuse to the forefront of public consciousness. Likewise, a recent rash of deaths at music events attributed to a substance called “molly” drew much attention to the proliferation of MDMA among recreational drug users and that compound’s possibly fatal consequences. And of course, more old-fashioned scourges such as heroin and cocaine continue to plague society.

But it is generally under-acknowledged that most drug abuse and the largest percentage of drug-related deaths flow from a single source: the misuse of prescription drugs. Legal opiates and other pharmaceuticals, so valuable as palliatives and curatives when taken as directed by medical authorities, are highly susceptible to misuse, and more easily obtainable than illegal substances, due to their justifiable marketplace proliferation. The following statistics illustrate the extent of the problem.

• Over 15 million people abuse prescription drugs, a larger population than those who abuse cocaine, hallucinogens, inhalants and heroin.
• Prescription drug abuse is responsible for the largest percentage of overdose deaths. Opioid painkillers accounted for 38.2% of the 22,400 drug overdose deaths in the U.S. in 2005. Factor in depressants and antidepressants, and one reaches 45%, more than cocaine, heroin, methamphetamine and amphetamines (39%) combined.
• But deaths alone do not fully constitute the cost to society. The year 2005 saw 1.4 million drug-related emergency room admissions, of which 598,542 were associated with abuse of pharmaceuticals alone or with other drugs.
• And abuse begins young, leading to a long lifetime of costs, with the average age for first such misuse hovering around 13-14, and the main source being family medicine cabinets^.1

In short, “Our nation is in the midst of a prescription drug abuse epidemic,” said Gil Kerlikowske, director of National Drug Control Policy.²

It is only natural and logical then that the FDA would decide to mandate new technologies — for both proprietary and generic products — which seek to ensure that opioids and other pharmaceuticals can resist and stymie misuse. And Congress has also begun to focus on this issue, offering such projected legislation as the STOPP Act of 2013.

The initial stage of FDA interest occurred in 2009 when the FDA first made clear that it would be incumbent upon manufacturers of high-potency opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol) to implement risk evaluation and mitigation strategies (REMS) by early 2012. Then, on Jan. 9, 2013, the federal agency released a draft guidance document titled “Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling.”

Reaffirming the epic nature of the crisis, FDA Commissioner Margaret A. Hamburg, M.D., said, “The FDA is extremely concerned about the inappropriate use of prescription opioids, which is a major public health challenge for our nation. This draft guidance is an important part of a larger effort by FDA aimed at preventing prescription drug abuse and misuse.”²

The FDA communiqué further explained, “Opioids can be abused in a number of ways. Abuse-deterrent formulations target the known or expected routes of abuse, such as crushing in order to snort or dissolving in order to inject, for the specific opioid drug substance in that formulation. The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving. In working with industry, the FDA will take a flexible, adaptive approach to the evaluation and labeling of potentially abuse-deterrent products.”

The industry wisdom on the available technologies eventually settled on six different approaches:

1. Incorporation of a gel-producing excipient that reacts to water, alcohol, or other common solvents.
2. Incorporation of a physical barrier such as hard plastic polymer coatings that resists tampering by crushing, dissolving, melting, or chemicals.
3. Chemically engineered prodrugs requiring in vivo enzymatic cleavage to achieve a pharmacological effect.
4. Binding in with the API an aversive ingredient along the lines of a flushing agent, emetic, diuretic, or other irritant that deters abuse by creating an unpleasant sensory experience.
5. Binding in with the API a sequestered antagonist agent that is released by unapproved usage.
6. Crafting a delivery system such as subdermal implants which renders the opioid inaccessible.

Various drug companies have explored these myriad formulations and tactics. Strategy number one outlined above seems the farthest along and most efficient, adaptable and easy to deploy, as we shall see. But the other tactics are also recording some success.

Method number two (physical barrier) is under research by a consortium of Pfizer, Pain Therapeutics and Durect. They are working to bring to market an Oxycodone gel capsule named Remoxy, which employs ORADUR technology that deters abuse by physical and chemical barriers that stand firm against crushing, freezing or dissolving.

Method number two also finds a powerful expression in the technology perfected by the German firm Grunenthal. “Grunenthal uses a polymer to make pills harder for drug abusers to crush and snort. If they try to dissolve the pills for injecting, they turn into a useless gel.”³ The technology is licensed to Purdue Pharma for its OxyContin line and to Endo Pharmaceuticals, which uses it in Opana.

Method number three (chemically engineered prodrugs) finds expression in New River Pharmaceutical’s NRP290, “a lysine-modified opiod prodrug that requires a biotransformation in the gastrointestinal tract to become active, deterring intravenous or intranasal administration,” according to the company’s website.

Method number four (binding a flushing agent to the API) is embodied by Acurox, from Acura and Pfizer, which incorporates niacin into its formulation. Ingested properly, the niacin is merely of nutritional value. But when abused, it produce intense flushing that drug abusers find aversive.

Method number five (sequestered API antagonist) is found in Embeda, a product of King Pharmaceuticals, which was acquired by Pfizer in 2010. Morphine sulfate and naltrexone hydrochloride are bound together, with the antagonist coming into play if the drug is misused. At the moment, however, issues of shelf life stability have caused a temporary withdrawal of the product while the issue is solved.

Method number six (delivery by subdermal implant) has been embraced by Titan Pharmaceuticals with its ProNeura technology involving the API Probuphine, or buprenorphine hydrochloride. A subdermal implant delivers six months of the drug without the possibility of tampering. Along vastly different lines, but also using a physical hurdle to prevent abuse, we find Collegium Pharmaceutical’s DETERx™. A DETERx gelcap contains myriad tiny spherical beads. The API is sequestered inside these beads and “uniformly dispersed in extended-release tamper-resistant matrix materials,” according to the company. The usual methods of abuse — chewing, crushing, heating — fail to release the API.

All of these technologies, however promising, have not yet quite reached the market-ready and highly adaptable perfection attained to date by the number one method, the abuse-triggered phase-change confinement of APIs in a gel-like form insusceptible to injection or insufflation.

Two firms lead the way in this arena: Altus Formulation, which recently partnered with CDMO Halo Pharma,; and QRxPharma, which has partnered with Aesica Pharmaceuticals, a UK-based CMO. Contract Pharma was privileged to speak with Dr. Damon Smith, chief executive officer of Altus, Dr. John W. Holaday, managing director, chief executive officer and chief scientific officer of QRxPharma; and Paul Titley, director of Business and Commercial Development at Aesica.

Dr. Smith’s involvement in this line of research extends back to his time at Labopharm, where the technology platform known as Intellitab first began. “It sprang out of our desire to provide the safest possible controlled-release tablets to our patients,” said Dr. Smith. “We realized that if patients inadvertently or deliberately broke their tablet, they could have (up to a whole day’s worth?) a lot of opioid drug getting into [their system] very quickly.” (This effect is commonly called “dose-dumping.”) To stop this occurring the first Intellitab product brought to the U.S. market by Dr. Smith and his team, uniquely allows once-a-day controlled release tablets to be broken but still release only the safe doses of drug at exactly the correct rate.⁴

Dr. Smith told us, “We then developed an extension of Intellitab technology to address not only inadvertent misuse, but deliberate abuse as well. Our clinical studies have now shown that even if you crush the pill, there is still no dose-dumping. Because we were always looking toward [the needs of] the legitimate patient population, we avoided things like antagonists that would stop your meds working if they seeped out, or deterrent agents that could make the legitimate patient feel ill.”

The Intellitab pill is very hard and durable to resist crushing. But lamentably, ingenious drug abusers can ultimately overcome that. Said Dr. Smith, “We’ve included a range of abuse-limiting systems in Intellitab technology. If you do manage to crush the tablet and add liquid, it reforms as a hard and insoluble gel. You can’t get that into a syringe and inject it. You have a pretty hard time trying to extract the drug from it as well, even with alcohol, liquids with different pHs, or solvents. We’ve shown that even an hour after crushing, less that 20% of drug was released in any of the solvents we’ve tested.”

The patented technology Altus uses to promote the phase change includes a superabsorbent system that sequesters liquids. Additionally, the API is encased in microparticles, which, like a tennis ball, deform but do not rupture when tampered with.

The Intellitab platform can be highly adaptable for both controlled-release and immediate-release formulations, or any combination of the two, as well as APIs of any molecular weight. Doses from five milligrams to over 700 milligrams have been clinically tested. Moreover, the technology is simple to manufacture on commonly available equipment and is highly reliable, as demonstrated by Altus’s partner, Halo. Working with Halo, “was a perfect fit for us,” said Dr. Smith. He sees a market for Intellitab not only in the U.S., but also in Canada and Europe, the latter two regions being rather slower to the table, but eager to “get ahead of the curve before [their national drug abuse] problems get to epidemic levels,” he remarked. “Given the breadth of the technology and the interest in the marketplace, we’d be foolish not to continue to focus in this area.”

Shortly before press time, Altus entered into a Development and Option Agreement with Zogenix, Inc. to develop abuse deterrent formulations of Zohydro ER using the Intellitab drug delivery platform. Zohydro ER (hydrocodone bitartrate) extended-release capsules, an opioid agonist, is the first approved extended-release oral formulation of hydrocodone without acetaminophen, for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Under the D&O Agreement, Altus has granted Zogenix an option to enter into an exclusive license on mutually agreed terms to develop and commercializeabuse deterrent formulations of Zohydro ER in the U.S. In connection with the transaction, Zogenix will pay Altus a technology access fee in the amount of $750,000. Zogenix will fund all development activities and Altus may earn an additional $3.5 million in development and regulatory milestones through to submission of an NDA. Following exercise of the option, Altus will be eligible to receive additional regulatory and sales milestone payments and royalties based on net sales of the licensed product.

In a press statement, Dr. Stephen Farr, president of Zogenix, remarked, “We conducted an extensive review of available abuse deterrent technologies and chose Intellitab because of its versatility, demonstrated abuse deterrent features, and Altus’ intellectual property portfolio. Of equal importance, Intellitab can be customized to match the current pharmacokinetic profile of Zohydro ER, which we believe, in turn, will allow us to bridge to the current product’s safety and efficacy established in the recently approved NDA and streamline overall development timelines.”

At QRxPharma, Dr. John Holaday said that his firm accepted the challenge of creating abuse-deterrent formulations head-on, without backing into it via a search for legitimate patient safeguards. The staggering numbers of overdose deaths prompted a realization of the need for such a technology. And in a bit of marketing genius, the sci-fi-sounding term “stealth beadlets™” was coined for its patented tech.

Dr. Holaday explained, “When abusers try to crush our tablets or dissolve them in alcohol or water (the typical ways abusers access the opioid), it releases a gel substance which inactivates the opioid so it cannot be snorted through the nasal mucosa or injected.”

Just how efficient are stealth beadlets at blocking opioids? Comparison tests performed on unmediated OxyContin and the newer, abuse-deterrent-formulation OxyContin tell the story. According to Dr. Holaday, “We could extract 95% [of the API] from the old OxyContin. We could extract 35% from the new OxyContin. But from ours, it’s only 12%. It both physically and chemically inactivates opioids.”

Stealth beadlets found immediate expression in QRxPharma’s dual opioid, MOXDUO CR, which is being developed for chronic pain. However, future use may also include stealth beadlets in MOXDUO IR. The company’s literature explained, “MOXDUO IR is targeted to be a first-line therapy for patients with moderate to severe acute pain, and is presently in registration with the FDA. [It’s] a patent-protected combination of morphine and oxycodone in 3mg/2mg, 6mg/4mg, 9mg/6mg and 12mg/8mg strengths” Dr. Holaday said that MOXDUO IR potentially offers “a significant reduction in side effects, [including] respiratory depression, vomiting and dizziness.”

Too often the abuse-deterrence discussion seems to revolve solely around opioids. But Dr. Holaday stressed that stealth beadlets pair up with any other abuse-prone drug. “Adderall, benzodiazepine, lithium, Valium, Halcion — this works [with them] as well.”

Getting stealth beadlet technology into the market falls on the shoulders of QRxPharma’s CMO partner, Aesica. Paul Titley emphasized Aesica’s reach, noting that the company, with 1,500 employees and approximately $250 million in sales, has the role of “creat[ing] almost any kind of dosage form with almost any kind of API.” And nowadays that includes “adjusting the formulations so that people who shouldn’t get their hands on certain products don’t get the hit they’re looking for.”

Enthusiastic about stealth beadlets, Mr. Titley laughingly referred to the exotic moniker as evoking a character from “Marvel comics or Lord of the Rings.” He praised the neutrality of the excipients under normal usage and their efficacy against abuse. Accidental abuse and harm such as respiratory depression caused by “Granny not reading the instructions on her packet” is also precluded by stealth beadlets.

Mr. Titley discussed why Aesica developed a relationship with QRxPharma rather than work internally on such efforts: “We’re rather impatient in developing our own IP [intellectual properties], so we go looking for IP that’s useful. Aesica can get more customers for this technique.”

No matter what technological approach is used, developers and manufacturers have to pay increased attention to this facet of their products. Abuse-deterrent formulations are not just a nice bells-and-whistles feature any longer. As Dr. Holaday remarked, “Frankly, if you’re a pharmaceutical manufacturer or a company that’s developing drugs for sale, this type of thing is not just nice to have, but now mandated by the FDA.”

Or, to hear Mr. Titley sum it up, “It’s a rolling process of symbiosis. The technology came first. Then the regulatory process accelerated the breadth of those technologies and the effectiveness of them. Now it’s a self-fulfilling prophecy. You can’t even consider going to the market without one of these technologies.” 

References

1. http://www.drugfreeworld.org/drugfacts/prescription/abuse-international-statistics.html
2. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm334785.htm
3. http://americannewsreport.com/nationalpainreport/fda-decision-could-mean-more-tamper-resistant-painkillers-8819436.html
4. http://www.fiercebiotech.com/press-releases/labopharm-provides-update-strategic-review-process

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Paul Di Filippo is a contributor to Contract Pharma. He can be reached at pgdf@cox.net.

Abuse-Deterrence News At CPhI Worldwide 2013, Catalent launched its new abuse-deterrent formulation offering. Catalent’s OptiGel Lock™ offers a multi-level abuse deterrence by including either: A gelling agent which, upon heating (a common practice prior to abuse via injection), solidifies, sequestering the API, and making the resulting mass difficult to syringe, or A high affinity resin which prevents extraction of the API until it is exposed to the pH of the gastric environment. It also includes a bubbling agent that “foams” upon aspiration, rendering any API extracted unavailable for injection. Since a softgel dose form is inherently difficult to grind or crush into a powder, this may eliminate the risk of abuse through inhalation. For the pharmaceutical market, OptiGel Lock technology may prevent injection abuse by decreasing syringeability, and inhalation. For the consumer market, the binding and bubbling technology can minimize the available API extracted, for example, preventing the diversion of native pseudoephedrine to methamphetamine.