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22 January 2018 Tablets & Capsules barrier to injection or to extracting a powder for insufflation. Of course, the excipients must be chosen to optimize deterrence to potential routes of abuse while still maintaining the targeted release profile. Fill materials may be soft, hard, waxy, or paste-like and may contain water-insoluble materials or suspended solids. These can modify the viscosity to prevent powdering and snorting, resist injection after moderate dilution, inhibit dose dumping in alcohol, and otherwise hamper extraction for use via alternative routes of administration. This ADF technology is highly flexible and comprises a number of elements that can be combined to maximize the abuse- deterrent properties and to provide the appropriate release profile. The elements include: • H i g h - m e l t i n g - p o i n t e x c i p i e n t s t h a t r e s i s t liquefaction at an injectable temperature, • Taste modifiers that resist covert administration, snorting, and dose dumping, • Water-insoluble excipients that resist extraction and adulteration by drinking, • Soluble excipients that allow release modulation, • Waxy excipients that resist dose dumping, snorting, and injection, • Viscosity modifiers that resist low-volume dissolution, injection, and dose dumping, and • Dyes that resist adulteration. An early example Some years ago Lonza developed an abuse-resistant ER levorphanol product—a potent opiate intended to treat severe pain. It was originally only available as an IR product, and the target product profile was set to allow once-daily dosing. The abuse profile was to resist abuse via injection, insufflation, and extraction. The development of this type of product starts with the ER element, which must be balanced against the abuse-deterrent properties. To make a liquid fill meet a circa 12-hour release profile, the most common approach is to use—as the primary mechanism of release—a thermo-softening waxy solid that contains a pore- forming material to allow diffusion. Additional solids are then used in order to modify the viscosity if there is an attempt to manipulate the formulation in low-volume solutions. A great deal of Category 1 characterization is then required to demonstrate the abuse-deterrent properties in the lab and to optimize both the abuse deterrence and release profile in harmony. For injection, the usual test method is to dilute the product in relatively low-volume solutions with different solvents and then to attempt to syringe it through various sizes of needle (Figure 3). For insufflation, tests seek to create particles that are of suitable size to be inhaled, with the size generally determined using a sieve (Figure 4). For liquid-based formulations, a range of powder flow enhancers are added to ensure the formulation is further challenged. Extraction in a range of solvents is also conducted, as this procedure can be used to directly abuse the drug load or to further manipulate it for abuse via other routes. Category 1 testing also calls for trials to ensure that dose dumping of the ER product will not occur if it is ingested with alcohol, as this also provides one of the most common accidental overdose routes (Figure 5) [7]. Finally, it must be shown that the product produces the clinical pharmacokinetics profile that is essential to ensure that the target product profile is met. In the levorphanol example, four prototype abuse-deterrent dosage forms of levorphanol ER were tested against the IR version of levorphanol in an analytically masked, fasted, single-dose five-way crossover bioavailability study. Fifteen healthy, non-smoking subjects aged 18 to 45 were assigned to each treatment period, with a 7- to 14-day washout between treatments. In conclusion, the formulation technology, regulation, and understanding in the area of prevention of abuse of prescription medications will continue to develop rapidly in the coming months and years. ADFs form one useful approach in the arsenal that is being generated to combat this abuse crisis. LFHC technology has been demonstrated to be a highly flexible and effective ADF option. T&C References 1. Florence et al. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Medical Care 2016 54(10): 901. 2. CDC. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2016. Available at http:// wonder.cdc.gov. 3 . F D A O p i o i d M e d i c a t i o n s p a g e . U S FDA>Drugs>Drug Safety and Availability>Information by Drug Class>Opioid Medications>Abuse-Deterrent Opioids. Available at https://www.fda.gov/Drugs/ DrugSafety/InformationbyDrugClass/ucm337066.htm. Click on the Abuse-Deterrent Opioids. 4. Statement from FDA Commissioner Scott Gottlieb. "FDA is taking new steps to help assess opioid drugs with abuse-deterrent properties," June 13, 2017. 5. Budman et al. Can abuse deterrent formulations make a difference? Expectation and speculation. Harm Reduction Journal 2009 6:8. 6. Abusolve is a trademark of Capsugel, a Lonza company. 7. Babul et al. Pharmaceutical development of novel, abuse deterrent extended release dosage forms of the multimodal analgesic levorphanol. European Journal of Pain Supplements, 5:S1, 280. Alyn McNaughton is a technical director at Lonza's MW Encap subsidiary, Units 4, 5, & 6, Oakbank Parkway, Livingston, West Lothian EH53 0TH United Kingdon. Website: www.lonza.com.