Issue link: https://www.e-digitaleditions.com/i/922724
Tablets & Capsules January 2018 21 Various controlled IR and ER drug products, such as opioids and morphine derivatives, antidepressants, and stimulants are at risk for abuse by melting or solubilizing the product and directly injecting, crushing, or snorting. For ER products, abusers simply chew or chemically extract the active compound and swallow the solution, making it instantly available for absorption. The roles of excipients Capsugel, now a Lonza company, has developed ADFs that allow encapsulated products to meet the target IR and ER profile while deterring the potential abuser from manipulating the drug substance in order to abuse the product through alternative routes of administration. This technology is built on Lonza's decades of experience in designing, developing, and manufacturing liquid-filled hard capsule (LFHC) products. LFHC technology provides a foundation to ADFs by using liquid and thermo-softening excipients that provide an immediate Additional approaches that provide enhanced deterrence are in development. However, it is important to appreciate that the required abuse-deterrent properties designed into a product are based on the specific mechanism(s) of potential abuse for that particular product. This can be related to dose dumping for ER products or even differences in bioavailability when administered by different routes. For example, as illustrated in Figure 2, Oxycontin (oxycodone) is commonly abused through oral, nasal, and injection routes but not through smoking [5]. Vicodin (hydrocodone bitartrate and acetaminophen) is predominately abused only orally, with a small number of abusers snorting it. Rarely is it injected or smoked. Fully understanding the abuse profile of a product is critical because by deterring one route of abuse, the product must not simply shift the abuser to an alternative abuse route that entails greater risks for the abuser. Switching an abuser from snorting to injection, for example, increases risk through exposure to HIV and other blood-borne diseases. Figure 5 Resistance to solvent extraction of abuse-deterrent ER forms of levorphanol [3] 120 100 80 60 40 20 0 120 100 80 60 40 20 0 In acid: In alcohol: Abuse-deterrent formulations Abuse-deterrent formulations Opiate ER reference Opiate ER reference Agitation in acid (0.1N HCl; pH 1.2) 240 rpm for 30 min Agitation in acid, then 95% ethanol (60 min, 30 min each at 240 rpm) Table 1 PK paramater LFHC test formulations versus IR reference-listed drug (levorphanol) IR levorphanol Form A Form B Form C Form D T max (h) 2.4 10.36 12.29 9.15 11.53 C max ratio (%) 100 40.89 29.97 32.01 26.66 AUC inf Ratio (%) 100 99.27 92.89 86.99 82.16 % decrease in abuse quotlent (C max /T max ) cf. IR formulation 90.6 95.2 91.6 94.5