Development of an in vitro system and model-based translational framework to assess haemolysis risk following intravenous abuse of medications containing polyethylene oxide.

Multiple cases of potentially life-threatening thrombotic microangiopathy (TMA) have resulted from intravenous abuse of medications containing polyethylene oxide (PEO), most often Opana ER (oxymorphone hydrochloride extended release). No validated models are available to assess the risk of TMA with different formulations and extraction methods following intravenous abuse. We have developed an in vitro system that involves passing pooled blood containing the excipient of interest through a syringe needle and assessing haemolysis via haemoglobin release. Haemolysis is induced by high shear stress caused by the flow of blood containing PEO through a narrow-bore syringe needle, recapitulating the mechanism in small blood vessels. Using the in vitro system, we demonstrate that high-molecular-weight PEO (>1 MDa) induces haemolysis in a concentration-dependent manner under flowing but not static conditions. We use data from the in vitro system and published in vivo data to predict the time course of the haemolytic response in vivo via a pharmacometric model. The in vitro system is a novel method for investigating factors influencing PEO-induced haemolysis. In combination with our model-based translational framework, the in vitro system allows straightforward assessment of the haemolytic potential of PEO-containing medications, and may find application in gauging TMA risk following intravenous abuse.

Application of hot-melt extrusion technology in immediate-release abuse-deterrent formulations.

OBJECTIVE: Hot-melt extrusion (HME) technology has been used for manufacturing extended-release abuse-deterrent formulations (ADFs) of opioid-type analgesics with improved tamper-resistant properties. Our objective was to describe application of this technology to immediate-release (IR) ADFs. DESIGN: For development of a sample IR ADF (hydrocodone 10 mg/acetaminophen 325 mg) based on HME, feasibility studies were performed using different excipients. The formulation selected for further development was evaluated via in vitro test battery. Moreover, in vivo performance of IR ADF technologies was investigated in an open-label, randomized, cross-over, phase 1, relative oral bioavailability study with another opioid (model compound). SETTING: Single-center bioavailability trial. PARTICIPANTS: Twenty-four healthy white male subjects. INTERVENTIONS: ADF IR formulation of an opioid and marketed IR formulation. MAIN OUTCOME MEASURE(S): For feasibility and in vitro studies, dissolution profiles, syringeability, particle size distribution after physical manipulation, and extractability were evaluated. For the phase 1 study, pharmacokinetic parameters were evaluated and compared for ADF IR and a marketed IR formulation. RESULTS: After manipulation, the majority of particles from the ADF IR formulation were >500µm and, thus, not considered suitable for intranasal abuse, while the majority of particles for the reference marketed IR formulation were <500µm. The ADF IR formulation was resistant to syringing and preparation for potential intravenous injection. In healthy subjects, pharmacokinetics of an ADF and marketed IR formulation of an opioid were nearly identical. CONCLUSIONS: Application of HME to IR formulations led to development of products with improved mechanical resistance to manipulation for intranasal or intravenous preparation, but similar bioavailability.

Evaluation of the tamper-resistant properties of tapentadol extended-release tablets: results of in vitro laboratory analyses.

OBJECTIVE: To evaluate tamper-resistant properties of tapentadol tablets formulated with polyethylene oxide (PEO) matrix. DESIGN: Analytical and physical tests to characterize tablets. INTERVENTIONS: Tapentadol extended release (ER) 50, 100, 150, 200, and 250 mg. MAIN OUTCOME MEASURE(S): Mechanical resistance of tapentadol ER tablets to crushing (all doses), in vitro drug-release profiles of intact and tampered 50- and 250-mg tablets, and resistance to extraction of 250-mg tablets subjected to hammering. RESULTS: Crush resistance testing showed no deformation of tablets with two metal spoons, minimal deformation (no pulverization/breakage) with a pill crusher, slight deformation with a standardized pharmacopeia breaking force tester, and flattening (no pulverization/breakage) with a standardized hammer instrument. Mean in vitro release profiles in quality control medium (0.050 M phosphate buffer, pH 6.8) were similar with intact and tampered (pill crusher) tablets; the release profile was faster for hammered than intact tablets, with 30 percent of the drug released after 30 minutes (slightly higher than maximum release allowed per drug product specifications). Intact tablets were completely resistant to extraction in most organic solvents tested; in aqueous solvents, the amount of drug extracted increased with time. Hammered tablets were less resistant to extraction but required vigorous shaking over extended periods of time to release >50 percent of active ingredient. CONCLUSIONS: In vitro results from tampering attempts presented herein demonstrate that tapentadol ER tablets were resistant to these forms of physical manipulation. Tapentadol ER tablets were also generally resistant to dissolution in most solvents. Developing tamper-resistant formulations is an important step in strategies to mitigate opioid abuse.

Opioid extended-release tablets with improved tamper-resistant properties.

OBJECTIVE: To prepare a polyethylene oxide-based tablet with high mechanical strength that would release an opioid for once- or twice-daily administration. This tablet would also create barriers against crushing and subsequent preparation steps for abuse and misuse that are not present in conventional opioid formulations. RESEARCH DESIGN & METHODS: Innovative manufacturing processes were created by applying heat and force simultaneously, using tramadol HCl as model compound; production scale testing used oxymorphone HCl. Standardized in vitro crush force and extraction tests were performed. RESULTS & DISCUSSION: A production scale manufacturing process using hot melt extrusion of a strand, cooling, slicing and shaping the slices into tablet form produced stable oxymorphone extended-release (ER) tablets with in vitro dissolution characteristics similar to commercial oxymorphone ER. The tablets resisted crushing by spoons, pill crushers and a hammer and resisted extraction in a test battery of solvents. The standardized tampering methods used here do not include all methods an abuser might employ. Postmarketing data will be needed to determine the actual impact of tamper resistance mechanisms on opioid abuse rates. CONCLUSIONS: This purely mechanical approach to tamper resistance may make a tablet less attractive for abuse without exposing compliant patients to new risks associated with opioid antagonists or aversive compounds. A compliant patient's risk of adverse events may be reduced by the tablet's resistance to accidental crushing.