Abuse-deterrent Properties Research Articles

Assessing Abuse-Deterrent formulations utilizing Ion-Exchange resin complexation processed via Twin-Screw granulation for improved safety and effectiveness

Opioid misuse is a public health crisis in the United States. In response, the FDA has approved drug products with abuse-deterrent features to reduce the risk of prescription opioid abuse. Abuse-deterrent formulations (ADFs) typically employ physical or chemical barriers or incorporate agonist–antagonist combinations as mechanisms to deter misuse. This study aims to assess the impact of abuse-deterrent properties, specifically ion-exchange resin complexation as a chemical barrier, on a model drug, promethazine hydrochloride (PMZ) tablets. Various formulations were developed through twin-screw wet granulation (TSWG) followed by twin-screw melt granulation (TSMG). In the TSWG process, the drug interacts with the resin through an exchange reaction, forming a drug-resin complex. Additionally, the study explored factors influencing the complex formation between the drug and resin, using the drug loading status as an indicator. DSC and ATR studies were carried out to confirm the formation of the drug-resin complex. Subsequently, hot melt granulation was employed to create a matrix tablet incorporating Kollidon® SR and Kollicoat® MAE 100P, thereby enabling sustained release properties. The drug-resin complex embedded in the matrix effectively deters abuse through methods like smoking, snorting, or parenteral injection, unless the drug can be extracted. In order to assess this, solvent extraction studies were conducted using an FDA-recommended solvents, determining the potential for abuse. Further investigations involved dissolution tests in change-over media, confirming the extended-release properties of the formulation. Results from dissolution studies comparing the ground and intact tablets provided positive evidence of the formulation's effectiveness in deterring abuse. Finally, alcohol-induced dose-dumping studies were conducted in compliance with FDA guidelines, concluding that the formulation successfully mitigates dose dumping in the presence of alcohol.

Oxycodone Extended-Release Capsule Utilization for Pain Management in a Cancer Palliative Care Clinic: A Retrospective Review

Xtampza ER™, an oxycodone extended-release capsule (OERC), was the first long-acting opioid to feature abuse-deterrent properties and various routes of administration without pharmacokinetic alterations. The primary objective of this study was to evaluate changes in reported pain scores after initiation of or rotation to OERC from a previous opioid. Baseline scores were from patients’ outpatient visits immediately before starting OERC and were compared to those at the next two follow-up visits. Secondary objectives identified variables that influenced pain scores. Methods included screening for cancer patients with outpatient OERC prescriptions seen in the palliative care clinic. Eighty-two charts were reviewed with 66 included. Overall mean pain scores at both follow-ups were lower than those at baseline (–0.7 ± 2.1; −1.1 ± 2.4). Results were statistically significant between first and second-reported pain scores versus baseline (p = 0.009; 0.012) but clinically insignificant, defined as a ≥ 2-point change in numeric pain scores. Most patients discontinued OERC at the first or second follow-up (35; 53%), and 12.1% of patients who started OERC were prescribed OERC at the end of the study. There were no significant variables identified to influence pain scores either statistically or clinically. Further studies are needed to determine the long-term efficacy and safety in cancer palliative-care patients.

Evaluating the effectiveness of reformulated extended-release oxycodone with abuse-deterrent properties on reducing non-oral abuse among individuals assessed for substance abuse treatment with the Addiction Severity Index-Multimedia Version (ASI-MV)

Objective Original brand extended-release (ER) oxycodone tablets (OC) for oral use were reformulated (ORF) with abuse-deterrent properties (ADP) against inhalation and injection routes in August 2010. This product transition provided an opportunity to compare “before and after” reformulation abuse trends. Our goal was to assess the change in abuse of brand oxycodone ER from before and after introduction of ORF. Methods Change in self-reported non-oral “OxyContin” abuse in the previous 30 days during two years pre- and four years post-reformulation was assessed among adults evaluated for substance use and treatment planning using the Addiction Severity Index-Multimedia Version (ASI-MV). Comparator opioids were used to provide a frame of reference for changes in abuse due to competing population-level opioid abuse interventions and other factors unrelated to the reformulation. A proportion (PR) and abuse report dispensing ratio (ARDR) are reported because a single measure of abuse has not been identified that can optimally describe opioid abuse or changes in opioid abuse. Results Interrupted time-series analyses indicated an immediate decline in non-oral abuse measures post-reformulation (PR = −52.1%; ARDR = −32.2%). Significant decreases from pre- to post-reformulation in non-oral abuse overall were observed (PR [95% CI] = −30.7% [-46.9%, −9.5%]; ARDR = −29.3% [-37.5%, −20.1%]). Comparator opioids did not demonstrate similar trends over the period. Conclusions Methodology applied in this study suitably assessed the effectiveness of an ADP product. Among individuals assessed for substance use, a differential decline in non-oral abuse of brand ER oxycodone was observed since introduction of ORF.

Stability of Abuse-deterrent properties of PEO-based Abuse-deterrent formulation

Abuse of opioid drug products is a national health crisis in the US. To deter abuse, a number of drug products with abuse-deterrent (AD) properties have been approved by the US Food and Drug Administration (FDA). For abuse deterrence, it is critical to maintain the AD properties during the product shelf life. However, no information on the stability of AD properties during product shelf life is publicly available. In this study, stability of AD properties of surrogate AD formulation (ADF) of opioid active pharmaceutical ingredients (APIs) were studied. Surrogate extended release (ER) AD tablets were prepared by direct compression using Diltiazem HCl (model drug), polyethylene oxide (PEO WSR 301) polymer and magnesium stearate followed by curing at 70 °C for 30 mins. The stability studies were conducted at 25 °C/60 % RH and 40 °C/75 % RH storage conditions for 12 months (M) and 6 months (M), respectively. In vitro characterization and evaluation of AD properties of tablets were performed. As anticipated, the curing process increased the crushing strength of the tablets. However, the tablets could still be manipulated and compromised leading to an enhancement in the amount of drug extracted in solvents (e.g., water, alcohol), regardless of extraction temperature as well as tablet storage condition and time. Furthermore, the granule particle size as well as viscosity in water of manipulated samples were found to be lower for tablets stored at 25 °C/60 % RH or 40 °C/75 % RH for 12 M or 3 M/6M, respectively. The changes in AD properties eased the syringeability of hydrated samples and ultimately led to the withdrawal of higher amounts of drug into the syringe, thereby, impacting the abuse deterrence potential of the formulation by an IV route. These data demonstrated that the stability of AD properties (i.e., granule particle size, viscosity and syringeability-injectability) of PEO-based tablets was dependent on the storage condition. In conclusion, the design of AD formulation and setting of product quality profile should take into consideration the stability of AD properties during the product shelf life.

Impact assessment of the variables affecting the drug release and extraction of polyethylene oxide based tablets

The overall objective of this research is to investigate the impacts of the polymer's molecular weight and source on the abuse deterrent properties of the PEO-based promethazine hydrochloride (PMZ HCl) tablets. Formulations were manufactured by hot-melt extrusion and direct compression, followed by curing. Thermal and mechanical manipulation techniques were applied and compared to the intact tablets. The prime mechanism of the drug release was found to be represented by the diffusion-controlled mechanism and the first-order model for the direct compressed and the hot-melt extruded whole tablets, respectively. A robust Artificial Neural Network (ANN) model was built, and a significance testing analysis was performed to identify the criticality and the impact of the investigated variables on the % release of the active pharmaceutical ingredient (API). The results showed that the use of the polymer from different suppliers had the lowest impact on the % release per time point. Furthermore, we observed that the tablets produced by hot-melt extrusion had faster release rates than tablets produced by direct compression. Moreover, the extraction studies showed that the % API recovered from the hot-melt extruded tablets was significantly higher than the direct compressed tablets regardless of the polymer molecular weight. The findings were attributed to the polymer's thermal degradation during the hot-melt extrusion process, which caused a reduction in solution viscosity and crystallinity of the polymer. The syringeability studies showed that it was relatively harder to withdraw the solution from the DOW samples; however, the % recovered API was higher than samples containing the polymer from Sumitomo Seika.

Effect of Manufacturing Process on the Retention of Abuse-Deterrent Properties of PEO-Matrix Tablets.

Polyethylene oxide (PEO) is a widely used polymer in the development of abuse-deterrent oral formulations. Different manufacturing processes including direct compression (DC) followed by sintering, wet granulation (WG) followed by compression and sintering, and hot melt extrusion (HME) can be used to manufacture abuse-deterrent oral drug products. Three different manufacturing processes (DC, WG, HME) were evaluated to test the retention of their abuse-deterrent features following attempts to grind the tablets or extrudates. In vitro drug release studies were conducted on 10% and 32% drug-loaded tablets/extrudates prepared using these manufacturing methods, and the release profiles from all formulations showed good extended-release properties. Drug content analysis on the granules obtained from tablets prepared by direct compression showed non-uniform drug distribution where an unexpectedly high drug content was present in the smallest size (< 250µm) granules, sizes which are likely to be inhaled by abusers. Granules from tablets prepared by wet granulation showed improved drug distribution across all granule sizes formed after grinding. Drug content testing on the granules obtained from extrudates prepared using hot melt extrusion showed excellent drug content uniformity along with sufficient strength to resist grinding into smaller particles. The retention of the abuse-deterrent properties of a dosage form following attempts to extract or abuse the drug is an important product characteristic, and the product design, formulation components, and manufacturing processes can all play critical roles in the retention of the desired abuse-deterrent properties.

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance.

BackgroundOver the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of “drug liking,” “take drug again”), which are referred to as ‘pharmacodynamic (PD)’ responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs.MethodsExtensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11th, 2010 until March 25th, 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data.FindingsFollowing oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65.InterpretationOur assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs.FundingThe study was partially funded by Fiscal Year 2017 Critical Path of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

Abuse-deterrent properties and cytotoxicity of poly(ethylene oxide) after thermal tampering

Poly(ethylene oxide) (PEO) is the most common deterring agent used in the abuse-deterrent formulations (ADFs). In this study, we investigated the PEO's abuse-deterrent properties and its potential cytotoxicity after being heated at high temperatures (80 °C and 180 °C). The results indicated a significant loss in both crush and extraction resistance features of the polymer, which is primarily associated with the polymer degradation at the higher temperatures. The heat-treated PEO at the high temperature was also found to lose its controlled-release feature, upon which over 80% of the drug was released after one hour in the simulated gastric fluid. The cytotoxicity of the PEO was further assessed to evaluate the safety of the polymer following the thermal treatment. Our findings revealed a substantial loss in the viability of the cells exposed to the PEO treated at higher temperatures. Taken all, heating PEO at high temperatures can lead to a significant loss in both the crush/extraction resistance characteristics and the safety of the polymer. These findings reemphasize the fact that more appropriate and stricter test and regulations will be needed to assure that the abuse deterrent formulations are safe and effective under severe conditions of abuse.

Abuse deterrent immediate release film technology (ADRIFT): A novel bilayer film technology for limiting intentional drug abuse.

Prescription opioid abuse also known as opioid epidemic has been an ever-growing problem in the United States. It has been associated with numerous emergencies and mortality with significant burden on healthcare system. Amongst various approaches proposed by FDA, development of an abuse deterrent formulation is one of the key strategies to address this opioid crisis. Existing abuse deterrent technologies have several deficiencies which enable abusers to manipulate/bypass it. The proposed study aims to develop and optimize an abuse-deterrent immediate release bilayer film (ADRIFT). A novel material with distinct process engineering was employed to achieve immediate drug release with nasal/intravenous abuse deterrent properties. Drug layer (DL) composed of a rapidly soluble film forming polymer - polyvinyl alcohol (PVA) while various solvent system and biocompatible polymers were screened to incorporate sodium polyacrylamide starch (KPX) in abuse deterrent layer (AL). Mechanical analysis of ADRIFT suggested that individual excipients played significant role in improving the mechanical strength of ADRIFT. Spontaneous formation of highly viscous gels in different solvents and resistance to mill into fine powder support the injection and snorting abuse deterrent potential, respectively. Immediate release (>85% release) was achieved in<30mins, indicating that there was no interference between either of the layers towards their specific purposes. Hence, our novel yet simple ADRIFT oral film technology could potentially be useful in manufacturing immediate release abuse-deterrent formulation of opioid drugs.

Use of Drug Release Testing to Evaluate the Retention of Abuse-Deterrent Properties of Polyethylene Oxide Matrix Tablets.

Abuse-deterrent formulations (ADFs) using physical/chemical barrier approaches limit abuse by providing resistance to dosage form manipulation to limit drug extraction or altered release. Standardizing in vitro testing methods to assess the resistance to manipulation presents a number of challenges, including the variation in particle sizes resulting from the use of various tools to alter the tablet matrix (e.g., grinding, chipping, crushing). A prototype, direct-compression ADF using a sintered polyethylene oxide (PEO) matrix containing dextromethorphan, an enantiomeric form of the opioid, levorphanol, was developed to evaluate testing methodologies for retention of abuse-deterrent properties following dosage form tampering. Sintered PEO tablets were manipulated by grinding, and drug content and release were evaluated for the recovered granules. Drug content analysis revealed that higher amounts of drug were contained in the smaller size granules (< 250μm, 190% of the theoretical amount) compared with the larger particles (> 250μm, 55-75% of theoretical amount). Release testing was performed on various size granule fractions (> 850μm, 500-850μm, 250-500μm, and < 250μm) using USP type I (basket), type II (paddle), and type IV (flow-through) apparatus. The USP type I and type II apparatus gave highly variable release results with poor discrimination among the release rates from different size granules. The observed sticking of the hydrated granules to the baskets and paddles, agglomeration of hydrated granules within the baskets/vessels, and ongoing PEO hydration with subsequent gel formation further altered the particle size and impacted the rate of drug release. The use of a flow-through apparatus (USP type IV) resulted in improved discrimination of drug release from different size granules with less variability due to better dispersion of granules (minimal sticking and aggregation). Drug release profiles from the USP type IV apparatus showed that the larger size granules (> 500μm) offered continued resistance to drug release following tablet manipulation, but the smaller size granules (< 500μm) provided rapid drug release that was unhindered by the hydrated granule matrix. Since < 500-μm size particles are preferred for nasal abuse, improved direct-compression ADF formulations should minimize the formation of these smaller-sized particles following tampering to maintain the product's abuse-deterrent features.

In vitro evaluation of a novel immediate-release formulation of oxy-codone (RoxyBond™) for the potential for abuse via injection.

Immediate-release (IR) oxycodone formulations may be manipulated for nonoral routes of administration. Oxycodone abuse-resistant immediate-release (ARIR) is a novel abuse-deterrent formulation (ADF) of IR oxycodone. This study aimed to assess the intravenous (IV) abuse potential of oxycodone ARIR relative to commercially available IR oxycodone tablets using in vitro laboratory studies. Intact or manipulated tablets were incubated in 5 or 10 mL of room temperature water for increasing amounts of time. For each timepoint, syringeability, defined as the ability to draw up water-immersed intact or manipulated tablets into a syringe, was assessed on a scale of 1 (very easy) to 10 (impossible). If the prepared sample could be drawn into a syringe, the proportion of syringeable oxycodone was measured analytically. In all conditions, it was nearly impossible to draw any liquid into a syringe from samples containing manipulated oxycodone ARIR tablets (N = 5/group), and most samples released very low concentrations (<10 percent) of their total oxycodone content, regardless of sample volume. In contrast, samples containing crushed IR oxycodone (N = 5/group) in small volumes of fluid were easily drawn into a syringe through the smallest needle, and more than 90 percent of the oxycodone content was released from relatively small sample volumes (5 mL). The difficulty required to prepare an injectable solution from oxycodone ARIR when manipulated suggests that oxycodone ARIR has abuse-deterrent properties that may deter IV abuse.

Development of Abuse-Deterrent Formulations Using Sucrose Acetate Isobutyrate.

The objective of the present investigation was to understand the effect of sucrose acetate isobutyrate (SAIB) on abuse-deterrent properties (ADPs) of abuse-deterrent formulations (ADFs) based on Polyox™. SAIB would enhance ADPs of Polyox™-based formulations due to its glassy liquid and hydrophobic properties. Formulations were prepared by granulation followed by compression and heat curing at 90°C. The formulations were evaluated for surface morphology, hardness, manipulation in coffee grinder, particle size distribution, drug (pseudoephedrine hydrochloride) extraction in water, alcohol, 0.1N HCl, 0.1N NaOH at room temperature and elevated temperature using microwave and oven, syringeability and injectability, and dissolution. The heat curing of formulations significantly increased the hardness (> 490N). Addition of SAIB imparted elasticity to formulations and decreased brittleness as indicated by lower values of work done and gradient compared to control formulations. After grinding, about 7.7-25.6% of the powder remained on the sieve (1mm pore opening), D90 was 53.1-136.7μm more, and Q (fraction < 500μm) was 17.8-40.7% less in SAIB-based formulations compared to control formulations. Drug extraction between control and test intact formulations was similar. However, drug extraction was 23.9-42.5% (water), 20.6-26.1% (0.1N HCl), and 37.4-50.6% (0.1N NaOH) less in SAIB-based powder cured and uncured formulations compared to control formulations. Dissolution varied from 65.6 ± 4.2 to 97.6 ± 4.0% in 9h from the formulations. In conclusion, addition of SAIB to Polyox™-based ADFs has synergistic effect on ADPs. This would further decrease potential of drug abuse/misuse by various routes.

3D printed opioid medicines with alcohol-resistant and abuse-deterrent properties.

In the past decade, prescriptions for opioid medicines have been exponentially increasing, instigating opioid abuse as a global health crisis associated with high morbidity and mortality. In particular, diversion from the intended mode of opioid administration, such as injecting and snorting the opioid, is a major problem that contributes to this epidemic. In light of this, novel formulation strategies are needed to support efforts in reducing the prevalence and risks of opioid abuse. Here, modified release tramadol printlets (3D printed tablets) with alcohol-resistant and abuse-deterrent properties were prepared by direct powder extrusion three-dimensional (3D) printing. The printlets were fabricated using two grades of hydroxypropylcellulose (HPC). Both formulations displayed strong ethanol-resistance and had moderate abuse-deterrent properties. Polyethylene oxide (PEO) was subsequently added into the formulations, which improved the printlets' resistance to physical tampering in nasal inhalation tests and delayed their dissolution in solvent extraction tests. Overall, this article reports for the first time the use of direct powder extrusion 3D printing to prepare drug products with both alcohol-resistant and abuse-deterrent properties. These results offer a novel approach for the safe and effective use of opioids that can contribute to the advantages that 3D printing provides in terms of on-demand dose personalisation.

Physical Barrier Type Abuse-Deterrent Formulations: Mechanistic Understanding of Sintering-Induced Microstructural Changes in Polyethylene Oxide Placebo Tablets.

The main goal of the presented work was to understand changes in the microstructure of tablets, as well as the properties of its main component viz. polyethylene oxide (PEO) as a function of sintering. Key polymer variables and sintering conditions were investigated, and sintering-induced increase in tablet tensile strength was evaluated. For the current study, binary-component placebo tablets comprised of varying ratios of PEO and anhydrous dibasic calcium phosphate (DCP) were prepared at two levels of tablet solid fraction. The prepared tablets were sintered in an oven at 80°C at different time points ranging from 10 to 900min and were evaluated for pore size, tablet expansion (%), and PEO crystallinity. The results showed that for efficient sintering and a significant increase in the tablet tensile strength, a minimum of 50% w/w PEO was required. Moreover, all microstructural changes in tablets were found to occur within 60min of sintering, with no significant changes occurring thereafter. Sintering also resulted in a decrease in PEO crystallinity, causing changes in polymer ductility. These changes in PEO ductility resulted in tablets with higher tensile strength. Formulation variables such as PEO level and PEO particle size distribution were found to be important influencers of the sintering process. Additionally, tablets with high initial solid fraction and sintering duration of 60min were found to be optimal conditions for efficient sintering of PEO-based compacts. Finally, prolonged sintering times were not found to provide any additional benefits in terms of abuse-deterrent properties.

A cellulose-based therapeutic polymer to deter intravenous drug abuse.

Prescription opioids have widely been abused as an epidemic. In this research, we developed a drug composition based on the crosslinked carboxymethylcellulose (XCMC) and a drug model that can effectively deter abuse by injection via multiple mechanisms. The anionic nature of the XCMC is responsible for complexing the cationic opioids in aqueous solutions, minimizing the free drug amount accessible for extraction. The crosslinked nature of the polymer is responsible for its swelling and partial containment of the drug solution within the swollen polymer's network, thus minimizing the available volume for subsequent injection. We have shown that XCMC can efficiently interact with cationic drugs in the form of physical blends and chemical complexes in different aqueous solvents, forming abuse-deterrent complexes. The complexation efficiency was affected by the solution pH and ionic strength, as well as the drug to polymer ratio in the formulation. The in vitro dissolution studies were conducted in two stages, the stage I in 0.1M HCl and the stage II in water and pH 7.5 phosphate buffer. These studies confirmed the proper drug release under the legitimate conditions of use. Therefore, the XCMC polymers have a great potential to be used as deterring agents in developing opioid medications with abuse-deterrent properties.

Polyethylene Oxide (PEO) Molecular Weight Effects on Abuse-Deterrent Properties of Matrix Tablets.

While polyethylene oxide (PEO)-based matrix tablets are frequently used as abuse-deterrent dosage forms, there is limited information available regarding how the selection of formulation components and manufacturing processes affect the resulting abuse-deterrent properties. The objective of the current study was to evaluate the effects of formulation and process variables on the abuse-deterrent features of PEO-containing tablets. Directly compressed tablets were prepared using three different PEO molecular weights (100,000; 900,000; and 5,000,000). As anticipated, sintering/thermal treatment above the melting point of PEO was crucial to impart crush-resistant features (tablet hardness > 500N). In addition to the sintering temperature, the weight fraction of PEO in the tablets affected their mechanical strength, and at least 50% w/w PEO was required to impart the desired crush-resistant features. In addition, the formulation and process variables also impacted syringeability and injectability of the PEO gels formed when the tablets were hydrated to simulate attempted drug extraction. High molecular weight PEO (900,000 and 5,000,000) produced gels more resistant to syringeability and injectability compared to low molecular weight PEO (100,000). Sintering above the polymer melting point decreased PEO crystallinity after cooling, and longer sintering times resulted in PEO degradation producing lower viscosity gels with reduced resistance to syringeability and injectability. Although sintering above the melting point of PEO imparts optimal mechanical strength to the tablets, prolonged sintering durations negatively impact polymer stability and alter the resulting abuse-deterrent features of the PEO-based tablet formulations.

Syringeability of morphine ARER, a novel, abuse-deterrent, extended-release morphine formulation

ABSTRACTBackground: Extended-release (ER) morphine formulations are commonly manipulated for non-oral routes of administration, particularly via injection. Morphine ARER, an abuse-deterrent formulation of ER morphine, has both physical and chemical properties that deter abuse. Objectives: To assess the syringeability of morphine ARER using in vitro laboratory studies. Methods: Intact, cut, or crushed morphine ARER tablets were incubated in 1, 5, or 10 mL of room temperature or 90°C water for 1, 5, 10, or 30 min of agitation. Crushed ER morphine tablets were assessed in 10 mL room temperature water. The difficulty to draw the mixture into a syringe was assessed on a scale of 1 (very easy) to 10 (impossible). If the prepared mixture was syringeable, released morphine was measured analytically. Results: Crushed and cut morphine ARER tablets formed a viscous material when subjected to a liquid environment and were rated as “impossible to syringe” in ≤5 mL water and were slightly syringeable in 10 mL water. In contrast, all syringeability tests of crushed ER morphine were rated as “very easy to syringe”. After 30 min in room temperature water, crushed ER morphine released 75% morphine whereas intact, cut, and crushed morphine ARER tablets released a maximum of 12%, 12%, and 5% of the total morphine content. Heating extractions resulted in increased morphine release. Conclusion: The difficulty to syringe morphine ARER when manipulated suggests that morphine ARER has abuse-deterrent properties that may deter intravenous abuse.

Real-world misuse, abuse, and dependence of abuse-deterrent versus non-abuse-deterrent extended-release morphine in Medicaid non-cancer patients

ABSTRACTObjective: Opioids with abuse-deterrent properties may reduce widespread abuse, misuse, and diversion of these products. This study aimed to quantify misuse, abuse, dependence, and health resource use of extended-release morphine sulfate with sequestered naltrexone hydrochloride (ER-MSN; EMBEDA®), compared with non-abuse-deterrent extended-release morphine (ERM) products in Medicaid non-cancer patients.Methods: Administrative medical and pharmacy claims data were analyzed for 10 Medicaid states from 1 January 2015, to 30 June 2016. Patients were included if they received a prescription for ER-MSN or any oral, non-abuse-deterrent ERM. Index date was the date of first prescription for an ER-MSN or ERM. Abuse/dependence, non-fatal overdose, emergency department (ED) visits, and ED/inpatient readmissions were determined for each participant. An overall measure of misuse and abuse was also calculated. To account for differences in follow-up, all counts are expressed per 100 patient-years.Results: There were 4,857 patients who received ER-MSN and 10,357 who received an ERM. The average age in the two cohorts was approximately 45 years old. From pre-index to follow-up, the number of patients per 100 patient-years with a diagnosis code indicating abuse or dependence increased by 0.91 (95% confidence interval [CI]: 0.85, 0.97) in the ER-MSN cohort and 2.23 (95% CI: 2.14, 2.32) in the ERM cohort. The number of patients per 100 patient-years with an opioid-related non-fatal overdose increased by 0.05 (95% CI: 0.04, 0.06) in the ER-MSN cohort compared with 0.11 (95% CI: 0.09, 0.13) in the ERM cohort. The opioid abuse overall composite score increased by 1.36 (95% CI: 1.24, 1.48) in the post-index period in the ER-MSN cohort compared to 3.21 (95% CI: 3.10, 3.32) in the ERM cohort.Conclusion: Misuse, abuse, and dependence events were numerically lower in patients receiving ER-MSN compared with those receiving ERM products.

An in vitro approach for evaluating the oral abuse deterrence of solid oral extended-release opioids with properties intended to deter abuse via chewing

The introduction of prescription opioids with abuse-deterrent (AD) properties to the marketplace has created a need for new testing methodologies to evaluate the performance of potentially abuse-deterrent opioid products. Drug abusers may attempt to chew solid oral extended-release (ER) opioids prior to ingestion to bypass the ER mechanism of the formulation to achieve euphoria. In the present study, a chewing apparatus was utilized to develop an in vitro chewing method for Hysingla ER tablets, a prescription opioid with labeling describing abuse deterrence via the oral route when chewed. Simulated chewing of Hysingla resulted in initially faster drug release during chewing while subsequent dissolution testing demonstrated that the masticated tablets still maintained ER properties. The degree of mastication and corresponding drug release were influenced by the compression gap and the resulting chewing forces. Simulated chewing followed by dissolution testing with different strengths of Hysingla indicated similar AD performance across strengths. By contrast, an opioid product with labeling that does not describe abuse-deterrent properties showed lower resistance to chewing resulting in higher drug release. The results of the present study suggest that the chewing methodology evaluated in this work may provide a useful in vitro tool for the comparative evaluation of AD properties.

Abuse-deterrent properties of REMOXY® ER, a high-viscosity extended-release oxycodone formulation.

These in vitro studies compared abuse-deterrent properties of REMOXY ER (extended-release oxycodone), a novel, high-viscosity gel formulation, versus the two currently marketed ER oxycodone formulations. Tampering methods were tailored to each product to maximize oxycodone release with the least complexity, time, and effort, based on the physical/chemical properties of each formulation. Oral abuse was simulated by extracting oxycodone from each manipulated formulation in Common Ingestible Liquids and in Advanced Solvents (not ingestible and requiring additional separation). To simulate injection abuse, oxycodone was extracted from each manipulated formulation in low volumes of injection vehicles, heated or unheated. Inhalation abuse potential was assessed by volatilization. In oral abuse simulations, manipulated REMOXY ER released 2-22 percent of its oxycodone in 20 minutes in five Common Ingestible Liquids, versus 77-85 percent oxycodone released from OxyContin® ER in 5 minutes in four of the five. In six Advanced Solvents, REMOXY ER released 3-37 percent at 20 minutes, versus 55-89 percent released from OxyContin ER at 5 minutes. Minimal oxycodone was extracted from REMOXY ER in five injection vehicles, heated or unheated. In contrast, OxyContin ER released 65-87 percent of its oxycodone within 10 minutes in all vehicles, regardless of heating. Xtampza® ER released 96 percent of its oxycodone in a heated injection vehicle and released 50-60 percent in two unheated injection vehicles. Showing minimal inhalation abuse potential, 9 percent of oxycodone was vaporized from manipulated REMOXY ER at 20 minutes compared to 8.8 percent at 5 minutes for OxyContin ER. In these studies, REMOXY ER demonstrated robust and meaningful abuse-deterrence relative to OxyContin ER and Xtampza ER. Abuse-deterrent drugs were intended to help fight opioid abuse. Yet, the persistence of the opioid epidemic indicates that vast improvements in abuse-deterrent technology are sorely needed. A new, high-viscosity, ER oxycodone formulation showed much improved abuse-deterrent properties in simulations of oral, injection, and inhalation abuse, compared to earlier, first-generation formulations.