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.

Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) vs Extended-Release Morphine Administered Intranasally in Nondependent Recreational Opioid Users.

OBJECTIVE: To compare the relative human abuse potential after insufflation of manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine ER tablets. METHODS: A randomized, double-blind, double-dummy, active- and placebo-controlled five-way crossover study was performed with adult volunteers who were experienced, nondependent, recreational opioid users. After intranasal (IN) administration of manipulated high-volume (HV) morphine-ADER-IMT (60 mg), participants were randomized (1:1:1:1) to receive IN manipulated low-volume (LV) morphine ER (60 mg), IN manipulated LV morphine-ADER-IMT, intact oral morphine-ADER-IMT (60 mg), and placebo in crossover fashion. Pharmacodynamic and pharmacokinetic assessments included peak effect of drug liking (E max ; primary endpoint) using drug liking visual analog scale (VAS) score, E max using overall drug liking, and take drug again (TDA) VASs scores, and mean abuse quotient (AQ), a pharmacokinetic parameter associated with drug liking. RESULTS: Forty-six participants completed the study. After insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT, drug liking E max was significantly lower ( P < 0.0001) compared with IN morphine ER. Overall drug liking and TDA E max values were significantly lower ( P < 0.0001) after insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT compared with IN morphine ER. Mean AQ was lower after insufflation of HV (9.2) and LV (2.3) morphine-ADER-IMT or ingestion of oral morphine-ADER-IMT (5.5) compared with insufflation of LV morphine ER (37.2). CONCLUSIONS: All drug liking, take drug again, and abuse quotient endpoints support a significantly lower abuse potential with insufflation of manipulated morphine-ADER-IMT compared with manipulated and insufflated non-AD ER morphine.

Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) versus Extended-Release Morphine Administered Orally in Nondependent Recreational Opioid Users.

Objective: To compare the relative human abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine sulfate ER tablets. Methods: This randomized, double-blind, triple-dummy, active- and placebo-controlled, 4-way crossover, single-center study included adult volunteers who were experienced, nondependent, recreational opioid users. Participants were randomized 1:1:1:1 to placebo, morphine-ADER-IMT (60 mg, intact), morphine-ADER-IMT (60 mg, manipulated), and morphine ER (60 mg, manipulated) and received 1 dose of each oral agent in crossover fashion, separated by ≥5 days. Pharmacodynamic and pharmacokinetic endpoints were assessed, including the primary endpoint of peak effect of Drug Liking (E max ) via Drug Liking Visual Analog Scale (VAS) score and the secondary endpoints of time to E max (TE max ) and mean abuse quotient (AQ; a pharmacokinetic parameter associated with drug liking). Results: Thirty-eight participants completed the study. Median Drug Liking VAS E max was significantly lower after treatment with manipulated morphine-ADER-IMT (67) compared with manipulated morphine ER (74; P = 0.007). TE max was significantly shorter after treatment with manipulated morphine ER compared with intact ( P < 0.0001) or manipulated ( P = 0.004) morphine-ADER-IMT. Mean AQ was lower after treatment with intact (5.7) or manipulated (16.4) morphine-ADER-IMT compared with manipulated morphine ER (45.9). Conclusions: Manipulated morphine-ADER-IMT demonstrated significantly lower Drug Liking E max compared with manipulated morphine ER when administered orally. Morphine-ADER-IMT would be an important new AD, ER morphine product with lower potential for unintentional misuse by chewing or intentional manipulation for oral abuse than currently available non-AD morphine ER products.

Sodium glycocholate transport across Caco-2 cell monolayers, and the enhancement of mannitol transport relative to transepithelial electrical resistance.

Ideally, the amount of enhancer remaining at the donor side during an in vitro transport study should be known, in order to know the true enhancer concentration during a permeability study. The purpose of the present study is to estimate the flux of the enhancer, sodium glycocholate (GC), through Caco-2 cell monolayers, and to study the effect of various enhancer concentrations on the permeability of GC itself, the permeability of mannitol and the transepithelial electrical resistance (TEER). Apical to basolateral permeability was measured with various concentrations 0.50% (10.2mM), 0.75% (15.5mM) and 1.00% (20.5mM) of GC. The GC permeabilities (Papp) were 4.7+/-1.1, 12.8+/-2.8 and 25.8+/-4.3 (x10(-7)cms(-1)), respectively. Mannitol transport changed accordingly with the Papp; 8.5+/-0.8, 9.9+/-2.7, 20.4+/-2.8 and 31.0+/-4.9 (x10(-7)cms(-1)) for GR, 0.50, 0.75 and 1.00% GC, respectively, with a TEER after 120min, relative to initial, of 86+/-6, 77+/-10, 61+/-11 and 49+/-7%. In conclusion a low and concentration-dependent permeability was found for GC across the Caco-2 cells. Mannitol transport increased and TEER decreased accordingly with increasing GC concentrations. TEER decreased in less than 10min to a certain level, without further reduction in a 120min period, indicating that the enhancer effect is momentarily, rather than time-dependent. The apical GC concentration and enhancer effect may be considered well defined during the experiment, due to the observed low permeability of GC.

Intranasal bioavailability of diazepam in sheep correlated to rabbit and man.

The purposes of the present study were to estimate the nasal bioavailability of diazepam in sheep and to compare this to earlier results in rabbits and humans. Additional, to compare the absorption during various initial periods in the two animal models and man, due to the importance of early absorption in emergency treatment. In a cross-over design, diazepam was nasally administered (7 mg) and intravenously (3 mg), respectively, to six sheep. Diazepam was solubilised in polyethylene glycol 300 in the nasal formulation. The mean nasal bioavailability, t(max) and C(max) were 15% (S.D.+/-8), 5 min (S.D.+/-3) and 934 ng/ml (S.D.+/-593), respectively. Sheep bioavailability was lower than rabbit 54% (P<0.001) and man 34% (P<0.05). In conclusion, the nasal absorption of diazepam was found to be fast, indicating the potential of nasal delivery in acute treatment. The initial (30 min) nasal bioavailability (30 min) for sheep and rabbit is a factor of 2.3 lower and 1.6 higher than man, respectively. The correlation of bioavailability was not optimal between sheep, man and rabbit with differences both in relation to extend and rate.