Governmental reports state that prescription drug abuse is the fastest growing drug problem in the United States, and a survey indicated that nearly one-third of people age 12 and above who used drugs illicitly for the first time in 2009 began by the non-medical use of a prescription drug. The problem is considered to have been exacerbated by the introduction of controlled-release opioid products that contain higher amounts of their active ingredients, beginning with an oxycodone product that was approved for marketing in 1995. Reports of overdosing and death from prescription pain products, especially the controlled-release oxycodone product, began to rise sharply in the early 2000s. A need clearly exists to improve the safety of opioid drug products, by making the products less susceptible for misuse.
In January 2013, the U.S. Food and Drug Administration published a draft guidance document for the evaluation and labeling of abuse-resistant opioid products. The guidance states that opioid analgesics can be abused by: swallowing whole in excessive quantities; crushing and swallowing; crushing and inhaling nasally (“snorting”); crushing and smoking; or crushing, dissolving, and injecting. Categories of abuse-resistant formulations were described as:
1. Physical barriers to prevent chewing, crushing, cutting, grating or grinding, and chemical barriers to resist extraction of the active ingredient with common solvents such as water, alcohol, and organic liquids.
2. Agonist/antagonist combinations that interfere with, reduce, or defeat the euphoria associated with abuse.
3. Aversion agents, by incorporating a substance that produces an unpleasant effect when the dosage form is altered before ingestion, or is ingested in a high dose.
4. Delivery systems that provide abuse resistance through release characteristic design or a mode of administration.
5. Prodrugs that lack opioid activity until acted upon in the gastrointestinal system.
6. Combinations of two or more of the foregoing.
The FDA describes the science of abuse deterrence as relatively new and rapidly evolving. A few abuse-resistant opioid products are currently approved for marketing. Some of these products are OxyContin® (oxycodone hydrochloride extended-release tablets), Targiniq® (oxycodone HCL+naloxone HCL), and Embeda® (morphine sulfate and naltrexone hydrochloride). Other products such as Suboxone® and Opana ER® (oxymorphone) also purport to have abuse deterrent properties but do not have a formal claim on the label. The mechanism for abuse deterrence range from physical barriers to the use of antagonists or abuse deterrent agents. For example, the Oxycontin® product sold by Purdue Pharma is formulated to have a high hardness to resist crushing, breaking, and dissolution, and also to form a viscous hydrogel in aqueous media that inhibits passage of an extract through a needle.
In general, abusers of opioid drugs will not simply ingest more than a typical therapeutic dose, since the controlled-release formulations do not provide bursts of drug bioavailability to create the desired euphoric sensations. Rather, abuse tends to involve some physical manipulation of a dosage form, so that larger amounts of immediately available drug can be taken orally, nasally, or by intravenous injection. For this reason, the OxyContin® tablets are formed from a partially molten mixture that contains a high molecular weight polyethylene oxide excipient; the result is a tablet that is not easily powdered and cannot readily be treated to form a solution that is capable of being injected. The very high hardness of this product, however, would not permit reproducible splitting of a dosage form to administer a reduced dose or improve the administration for those having difficulty in swallowing.
Despite the availability of a few products with abuse deterrent properties, the abuse of prescription medicine is still on rise and the serious abusers can bypass the deterrent mechanism to extract the drug by more sophisticated manipulation. Novel technologies are needed so that these important classes of medicines can be made available to the patients while lowering the risk of abuse and diversion for these products. In particular, new formulations are needed which can be used with immediate release pharmaceutical products.
New formulations, while having abuse-resistant properties, must also allow for the active pharmaceutical ingredient to be soluble in the gastrointestinal tract and have the desired pharmacological activity. In the case of opioids, the pharmacological activity would be an analgesic effect.