Clinical relevance of the pharmacokinetic characteristics of an abuse-deterrent, extended-release, injection-molded morphine tablet.

OBJECTIVE: To characterize the pharmacokinetics (PK) and in vitro alcohol dissolution characteristics of extended-release (ER), injection-molded (IM) morphine tablets with abuse-deterrent (AD) features (morphine-ADER-IMT). DESIGN: In vivo, in vitro, and in silico studies were conducted. A randomized, two-cohort study evaluated the bioequivalence of morphine-ADER-IMT (60 mg) to morphine ER (60 mg; MS Contin®; Purdue Pharma LP, Stamford, CT) and characterized the effect of food on the PK profile of morphine-ADER-IMT. A three-treatment, three-period crossover study assessed the bioequivalence of morphine-ADER-IMT (30 and 2 ȕ 15 mg) to morphine ER (30 mg). Bioequivalence studies were performed in healthy male and female subjects (18-55 y of age) in the presence of naltrexone blockade. PK modeling was performed to assess steady-state bioequivalence for morphine-ADER-IMT 60 mg compared with morphine ER 60 mg. In vitro alcohol dissolution studies were performed with morphine-ADER-IMT (15 and 60 mg). RESULTS: Fifty-nine and 56 subjects completed the 60-mg bioequivalence/food effect study and 30-mg bioequivalence study, respectively. Bioequivalence of morphine-ADER-IMT 60, 30, and 2 ȕ 15 mg and morphine ER was demonstrated to comparable doses of morphine ER. No clinically significant food effect was observed with morphine-ADER-IMT. Treatment-emergent adverse events were similar among all treatment groups. Steady-state modeling indicated bioequivalence between morphine-ADER-IMT 60 mg and morphine ER 60 mg when administered every 8 or 12 hours. No evidence of alcohol dose-dumping was observed with morphine-ADER-IMT. CONCLUSIONS: Morphine-ADER-IMT, an ER morphine formulation with robust AD features, has a clinical PK profile that is well suited for patients with chronic pain.

The ALERRT® instrument: a quantitative measure of the effort required to compromise prescription opioid abuse-deterrent tablets.

BACKGROUND: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT® instrument (PinneyAssociates; Bethesda, MD) uses visual analog scales to assess the labor, effort, and resources necessary to physically compromise AD product candidates in standardized settings. OBJECTIVE: Use the ALERRT® instrument for testing morphine abuse-deterrent, extended-release, injection-molded tablets (ADER-IMT) 60 and 100 mg and the comparators immediate-release (IR) morphine sulfate 30 mg and extended-release (ER) morphine sulfate 60 mg. METHODS: Four technicians tested the products using 10 household tools. The ALERRT instrument quantified effort (all tools) and time (3 preselected tools) required for manipulation. RESULTS: Morphine-ADER-IMT 60 and 100 mg were difficult to manipulate, as demonstrated by high scores (mean range, 71.0-99.0 and 77.0-99.5, respectively). IR and ER morphine sulfate were easy to manipulate (low scores; mean range, 2.0-14.8 and 2.3-17.5, respectively). Statistically significant mean differences between morphine-ADER-IMT and comparators' ALERRT scores were observed. Manipulations of morphine-ADER-IMT 60 and 100 mg for 300 seconds failed to produce substantial powdering. Manipulations of IR morphine sulfate (mean range, 65.5-175.8 seconds) and ER morphine sulfate (49.3-163.0 seconds) produced substantial to complete powdering in 92% of tablets. CONCLUSIONS: Morphine-ADER-IMT was extremely difficult to manipulate versus non-AD formulations of morphine. The ALERRT system differentiated the degree of effort for manipulation of morphine-ADER-IMT and non-AD morphine formulations, indicating sensitivity of this instrument as part of Category 1 testing. By measuring the degree of effort required for manipulation, the ALERRT instrument provides an empirical assessment into the relative difficulty of manipulating opioid analgesics for abuse.

Abuse-deterrent features of an extended-release morphine drug product developed using a novel injection-molding technology for oral drug delivery.

OBJECTIVE: A novel technology platform (Guardian™ Technology, Egalet Corporation, Wayne, PA) was used to manufacture morphine abuse-deterrent (AD), extended-release (ER), injection-molded tablets (morphine-ADER-IMT; ARYMO® ER [morphine sulfate] ER tablets; Egalet Corporation), a recently approved morphine product with AD labeling. The aim of this article is to highlight how the features of Guardian™ Technology are linked to the ER profile and AD characteristics of morphine-ADER-IMT. RESULTS: The ER profile of morphine-ADER-IMT is attributed to the precise release of morphine from the polymer matrix. The approved dosage strengths of morphine-ADER-IMT are bioequivalent to corresponding dosage strengths of morphine ER (MS Contin®; Purdue Pharma LP, Stamford, CT). Morphine-ADER-IMT was very resistant to physical manipulations intended to reduce particle size, with <10 percent of particles being reduced to <500µm, regarded by the US Food and Drug Administration as a relevant cutoff for potential insufflation in their generic solid oral AD opioid guidance. Furthermore, morphine was not readily extracted from the polymer matrix of morphine-ADER-IMT in small- or large-volume solvent extraction studies that evaluated the potential for intravenous and oral abuse. CONCLUSIONS: The ER profile and AD characteristics of morphine-ADER-IMT are a result of Guardian™ Technology. The combination of the polyethylene oxide matrix and the use of injection molding differentiate morphine-ADER-IMT from other approved AD opioids that deter abuse using physical and chemical barriers. The high degree of flexibility of the Guardian™ Technology enables the development of products that can be tailored to almost any desired release profile; as such, it is a technology platform that may be useful for the development of a wide range of pharmaceutical products.