A review on abuse-deterrent formulations: formulation technology and regulatory stands in approval process.

Drug abuse has become a global health problem over the past few years. Opioid abuse increased with an increase in the prescription of opioids for pain management. Many other classes of drugs are also abused and misused like anti-depressants, stimulants, hallucinogens, anti-psychotic, and anticholinergic drugs. One of the major reasons is that patients falsely diagnosed with depression, anxiety, and severe pain are prescribed these drugs, which are likely to be addictive. Abuse-deterrent formulations are one means to control drug abuse and overdose of prescription opioids. In this review, we explained how abuse-deterrent technology works, key ingredients used in abuse-deterrent formulations, a brief about marketed opioid drug products with abuse-deterrent properties, and the stand of regulatory agencies in the approval process of opioid drug products. In the end, it summarized that pharmaceutical industries and the FDA put their efforts into reducing drug abuse by encouraging the development of ADFs. Most available drug product having abuse-deterrent features contains Polyethylene oxide, which degrades at high temperatures. It requires the attention of the researcher to find an alternate ingredient or process to overcome said problem. From a regulatory point of view, only a few regulatory agencies have published their guidance on ADFs. It is important to convey other regulatory organizations' perspectives on ADFs as well.

A Chewing Study of Abuse-Deterrent Tablets Containing Polyethylene Oxide Using a Robotic Simulator.

Abuse-deterrent formulations (ADFs) refer to formulation technologies aiming to deter the abuse of prescription drugs by making the dosage forms difficult to manipulate or extract the opioids. Assessments are required to evaluate the performance of the drugs through different routes including injection, ingestion, and insufflation and also when the drugs are manipulated. Chewing is the easiest and most convenient way to manipulate the drugs and deserves investigation. Chewing is one of the most complex bioprocesses, where the ingested materials are subject to periodic tooth crushing, mixed through the tongue, and lubricated and softened by the saliva. Inter- and intra-subject variations in chewing patterns may result in different chewing performances. The purpose of this study is to use a chewing simulator to assess the deterrent properties of tablets made of polyethylene oxide (PEO). The simulator can mimic human molar grinding with variable chewing parameters including molar trajectory, chewing frequency, and saliva flow rate. To investigate the effects of these parameters, the sizes of the chewed tablet particles and the chewing force were measured to evaluate the chewing performance. Thirty-four out of forty tablets were broken into pieces. The results suggested that the simulator can chew the tablets into smaller particles and that the molar trajectory and saliva flow rate had significant effect on reducing the size of the particles by analysis of variance (ANOVA) while the effect of chewing frequency was not clear. Additionally, chewing force can work as an indicator of the chewing performance.

Self-regulated Anti-Overdose Crush and Extraction-Resistant Drug Delivery System to Combat Opioid Overdose Crisis.

Pharmaceutical opioid dosage forms are commonly misused via an oral route in non-manipulated form, i.e., overdose in intact form, or manipulated form, i.e., after crushing the dosage form, and also via the non-oral route in manipulated form, particularly the parenteral or nasal route. To assess the self-regulated anti-overdose property, crushing strength, extractability, and syringeability of the developed drug delivery system by in vitro laboratory studies. Tapentadol HCl drug particulates fabricated using different polymers were assessed for extractability studies in 25 ml of water at room temperature (RT) and at > 90°C. Crushing strength was assessed by grinding the drug particulates in a mortar and pestle and a coffee grinder for 1 min. For syringeability, an attempt was made to withdraw the drug mixture using a 1 ml insulin syringe for 1 min. To assess the self-regulated anti-overdose property, in vitro dissolution testing on a single-capsule per dissolution vessel (normal condition) and four-capsules per dissolution vessel (overdose condition) was performed. POLYOX, Natrosol, and Blanose-containing drug particles retarded drug extraction by > 80% at RT and > 90°C. After 1 min of grinding in a mortar and pestle and a coffee grinder, crushed POLYOX-containing drug particulates were retained at > 99% on the ASTM-170# screen. The attempt to withdraw the viscous mixture of drug formulation prepared with 5 ml of water for 1 min using a 1 ml insulin syringe was unsuccessful. In dissolution studies, more than 90% of the drug was released in normal conditions, and more than 90% of the drug was retarded in overdose conditions. In vitro laboratory studies demonstrate that the developed self-regulated anti-overdose crush-resistant drug delivery system may deter misuse via oral and non-oral routes.

Assessing Drug Release from Manipulated Abuse Deterrent Formulations.

There is a need to develop in vitro dissolution methods that discriminate for particle size of the manipulated abuse deterrent formulation (ADF) and that can be used for in vivo predictive models since dissolution methods developed for intact formulation might not be suitable for manipulated ones. A vertical diffusion cell (VDC) and United States Pharmacopeia (USP) Apparatus 1, 2, and 4 were evaluated for measuring the dissolution of intact and manipulated metoprolol succinate tablets with abuse deterrent-like properties. These tablets were physically manipulated to produce fine (106-500 µm) and coarse (500-1000 µm) powder samples. The VDC method was not able to discriminate the effect of particle size on drug release with varied stirring rate (200 to 800 rpm), molecular weight cut-off (MWCO, 3-5 kDa to 12-14 kDa) of the diffusion membrane, or composition and ionic strength (0.45% and 0.9%) of receiver medium. Standard and modified USP Apparatus 1 and 2 methods were assessed; however, large variations (RSD > 20%) were observed with USP Apparatus 1 for manipulated product dissolution and floating powder samples caused failure of auto-sampling when using standard USP Apparatus 2. For the USP Apparatus 4 dissolution method, packing configuration (1, 3, 8 layers and blend), ionic strength of dissolution medium (0.017, 0.077, and 0.154 M additional NaCl), and flow rate (4, 8, 16 mL/min) were studied to discriminate the effect of particle size on release. The USP Apparatus 4 dissolution method was optimized by using a packaging configuration of 8 layers with 8 mL/min flow rate which exhibited low variability and complete drug release and it could be used for in vivo predictive models. The dissolution method variables can be optimized for a specific product for desirable reproducibility and discriminatory power when using USP Apparatus 4.

Overdose and Alcohol Sensitive Immediate Release System (OASIS) for Deterring Accidental Overdose or Abuse of Drugs.

Death from an accidental or intentional overdose of sleeping tablets has increased exponentially in the USA. Furthermore, the simultaneous consumption of sleeping tablets with alcoholic beverages not only intensifies the effect of sleeping tablets but also leads to blackouts, sleepwalking, and death in many cases. In this article, we proposed a unique and innovative technology to prevent multi-tablet and alcohol-associated abuse of sleeping tablet. Agonist- and antagonist-loaded polymeric filaments of appropriate Eudragit® polymers were prepared using hot melt extrusion. Metoprolol tartrate and hydrochlorothiazide were used as model drugs in place of zolpidem tartrate (agonist-BCS class I) and flumazenil (antagonist-BCS class IV), respectively. Crushed filaments were converted into a tablet with a novel rapidly soluble co-processed alkalizing agent. Dissolution studies of single tablet and multiple tablets (5) in fasted state simulated gastric fluid (FaSSGF) confirmed that the release of the agonist was significantly (p < 0.0001) reduced in multi-tablet dissolution. Furthermore, the release of antagonist was significantly higher when tablet was exposed to FaSSGF+20% ethanol and various alcoholic beverages. Thus, appropriate use of Eudragit® polymer's chemistry could help design a tablet to prevent the release of agonist in case of overdose and simultaneous release of antagonist when consumed with alcohol.

Evaluation of Abuse-Deterrent Characteristics of Tablets Prepared via Hot-Melt Extrusion.

In this study, the effect of formulation variables and process parameters on the abuse-deterrent (AD) characteristics of a matrix tablet manufactured using hot-melt extrusion (HME) was investigated. The formulation variables included polyethylene oxide (PEO) grades and its input level, while the HME process parameters varied were barrel temperature profile and die diameter. Depending on the diameter of the extrudate (2.5 mm or 5.0 mm), two different downstream processes were used to prepare the tablets: cryo-milling followed by compression for the 2.5 mm extrudate, and cutting followed by compression for the 5.0 mm extrudate. A D-optimal statistical design was used to evaluate the impact of formulation and process parameters on various responses, including tablet physical strength, particle size after manipulation, syringeability and injectability, solution viscosity, extractability in solvents, and dissolution rates. It was found that the post-HME extrusion processing method played a critical role in affecting the AD characteristics of abuse-deterrent formulations, likely through changing the tablet compactability and porosity. When the extrudates were cryo-milled-compressed, the tablets could be readily manipulated by milling, which led to high degree of extractability. Under high alcohol concentration, burst drug release was observed for the tablets compressed from cryo-milled extrudates. Additionally, heat exposure during HME process caused significant drop in PEO solution viscosity, likely due to thermal degradation.

Mitigation of IV Abuse Through the Use of Abuse-Deterrent Opioid Formulations: An Overview of Current Technologies.

Providers who treat patients with chronic pain face a dual challenge: providing adequate access to opioid therapies for appropriate pain management while adopting strategies to minimize the risk for abuse. Commonly prescribed opioids have substantial abuse potential when administered intravenously, and extended-release (ER)/long-acting (LA) opioids may be targeted for IV abuse because of the higher per-dose medication level. The consequences of IV opioid abuse are severe and increase the risks for adverse outcomes, including mortality due to acute health events, serious infections, and deep vein thrombosis, to name a few. To reduce the potential for abuse of prescription opioids by both recreational and experienced drug abusers, abuse-deterrent formulations (ADFs) of opioid medications employ either physical/chemical barriers or agonist-antagonist combinations. Here we review the development and use of opioid ADFs as a harm-reduction strategy, and their potential for mitigating IV opioid abuse. The approved ER/LA opioids with ADF labeling in the United States include formulations of oxycodone, hydrocodone, and morphine. Findings from in vitro laboratory tests of abuse deterrence for opioid ADFs are described herein, as are data from human abuse potential studies for IV abuse of those ADF products, for which such studies are feasible (ie, abuse-deterrent agonist-antagonist formulations). The available ADF opioids may decrease both the attractiveness and the feasibility of IV abuse. The adoption of ADF opioids represents one tactic for providing access to needed medication for patients with chronic pain, while potentially reducing the risk for opioid abuse, in a comprehensive effort to combat the opioid epidemic.

Pain Control in the Presence of Drug Addiction.

Drug addiction is present in a significant proportion of the population in the USA and worldwide. Drug addiction can occur with the abuse of many types of substances including cocaine, marijuana, stimulants, alcohol, opioids, and tranquilizers. There is a high likelihood that clinicians will encounter patients with substance abuse disorders on a regular basis with the prevalence of the use of illicit substances and the high rate of abuse of prescription drugs. The use of abuse deterrent formulations of prescription opioid agents, pill counts, and urine drug abuse screenings are all useful strategies. Optimum pain management of patients with addiction in the outpatient and inpatient setting is essential to minimize pain states. Careful selection of medications and appropriate oversight, including drug agreements, can reduce drug-induced impairments, including sleep deficits and diminished physical, social, and sexual functioning. This review, therefore, discusses the prevalence of illicit and prescription drug addiction, the challenges of achieving optimum pain control, and the therapeutic approaches to be considered in this challenging population. More research is warranted to develop improved therapies and routes of treatments for optimum pain relief and to prevent the development of central sensitization, chronic pain, and impaired physical and social functioning in patients with drug addiction.

The role of abuse-deterrent formulations in countering opioid misuse and abuse.

WHAT IS KNOWN AND OBJECTIVE: Pain is a prevalent, and due to the ageing population, increasing medical problem. Opioids are frequently prescribed to meet the unmet medical need. Unfortunately, with the increase in the legitimate use of opioids, there has been a corresponding increase in abuse. A practical way to retain the pain relief afforded by opioids while decreasing opportunities for abuse is to make it more difficult to extract the opioid from the product or to make it less desirable to do so by designing an abuse-deterrent formulation (ADF). We provide a brief overview of the strategies and early evidence related to opioid ADFs. METHODS: Published and unpublished literature, websites, and other sources were searched for current opioid formulation options, including immediate-release and extended-release products. Each was summarized, reviewed and assessed. RESULTS: The strategies that have been used to design the current opioid ADFs involve one or more of four approaches: a physical barrier; incorporation of an opioid receptor antagonist (e.g. naloxone) that self-limits opioid action when taken in excess amount; inclusion of a noxious agent that is released during inappropriate use; or a pro-drug. WHAT IS NEW AND CONCLUSIONS: Legitimate use of opioid analgesics carries with it certain risks, including the risk of abuse. The new ADFs utilize four major strategies and provide innovative additions to the armamentarium. They likely will become an important part of a comprehensive approach to limiting, although not eliminating, opioid misuse and abuse.

Extended-release hydrocodone: the devil in disguise or just misunderstood?

Opioid abuse in the United States increased significantly over the past decade, leading to opioid-related deaths. Approval of Zohydro ER, a product that lacks an abuse-deterrent formulation, has provoked media controversy and aggressive legislative action from multiple stakeholders. Only the American Academy of Pain Management has released a position statement on this medication, and individual opinion varies. Additional single-entity extended-release hydrocodone formulations are in the pipeline, and Zohydro ER's limited clinical utility may make the controversy associated with its approval a moot point. As with other opioids, providers will need to assess individual patient risk versus benefit when prescribing Zohydro ER.

Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation.

OBJECTIVE: The reformulation of oxycodone hydrochloride controlled-release (CR) tablets in August 2010 created a natural experiment at a national scale, providing an opportunity to evaluate patterns of abuse of prescription opioids and other drugs before and after introduction of this abuse-deterrent formulation (ADF). DESIGN: Observational, cross-sectional study SETTING: Sentinel sample of adults assessed for substance abuse treatment within the NAVIPPRO® surveillance system SUBJECTS: Two hundred thirty-two thousand and eight hundred seventy-four adults at 437 facilities during January 1, 2008 through December 31, 2011. METHODS: Time-series analysis using logistic regression to estimate quarterly prevalence of past 30-day abuse (adjusted for covariates and prescription volume) and changes in abuse pre-and post-ADF introduction. RESULTS: Increases in abuse prevalence occurred for all prescription opioids as a class and for extended-release (ER) opioids. Significantly greater abuse of ER oxymorphone and buprenorphine occurred in the post-ADF period (relative risk [RR] = 2.91, 95% confidence interval [CI] = 2.59-3.27 and RR = 1.85, 95% CI = 1.74-1.96). Increases in abuse for these two compounds were significant among groups who reported abuse via preferential routes of administration (oral only, snorting only, injection only) post-ADF introduction. CONCLUSIONS: Replacement of a widely prescribed opioid formulation known for its abuse potential alone may have had little impact on overall rates of prescription opioids as a class. However, changes in abuse levels of certain opioids coinciding with ADF introduction suggest possible switching of abuse among this study sample to specific long-acting opioid analgesics. Additional follow-up studies will be important to monitor changing abuse patterns and their public health impact as new opioid formulations are developed and introduced to market.

Preclinical Models of Attention Deficit Hyperactivity Disorder: Neurobiology, Drug Discovery, and Beyond.

OBJECTIVE: We offer an overview of ADHD research using mouse models of nicotine exposure. METHOD: Nicotine exposure of C57BL/6 or Swiss Webster mice occurred during prenatal period only or during the prenatal and the pre-weaning periods. Behavioral, neuroanatomical and neurotransmitter assays were used to investigate neurobiological mechanisms of ADHD and discover candidate ADHD medications. RESULTS: Our studies show that norbinaltorphimine, a selective kappa opioid receptor antagonist is a candidate novel non-stimulant ADHD treatment and that a combination of methylphenidate and naltrexone has abuse deterrent potential with therapeutic benefits for ADHD. Other studies showed transgenerational transmission of ADHD-associated behavioral traits and demonstrated that interactions between untreated ADHD and repeated mild traumatic brain injury produced behavioral traits not associated with either condition alone. CONCLUSION: Preclinical models contribute to novel insights into ADHD neurobiology and are valuable tools for drug discovery and translation to benefit humans with ADHD.

Multidimensional opioid abuse deterrence using a nanoparticle-polymer hybrid formulation.

Misuse of prescription opioid drugs is the leading cause of the opioid crisis and overdose-related death. Abuse deterrent formulations (ADFs) have been developed to discourage attempts to tamper with the formulation and alter the ingestion methods. However, abusers develop complex extraction strategies to circumvent the ADF technologies. For comprehensive deterrence of drug abuse, we develop tannic acid nanoparticles (NPs) that protect encapsulated opioids from solvent extraction and thermal challenge (crisping), complementing the existing formulation strategy to deter injection abuse. Here, we develop a hybrid ADF tablet (NP-Tab), consisting of iron-crosslinked tannic acid NPs encapsulating thebaine (model opioid compound), xanthan gum, and chitosan (gel-forming polymers), and evaluate its performance in common abuse conditions. NP-Tab tampered by crushing and suspended in aqueous solvents forms an instantaneous gel, which is difficult to pull or push through a 21-gauge needle. NPs insulate the drug from organic solvents, deterring solvent extraction. NPs also promote thermal destruction of the drug to make crisping less rewarding. However, NP-Tab releases thebaine in the simulated gastric fluid without delay, suggesting that its analgesic effect may be unaffected if consumed orally as prescribed. These results demonstrate that NP-Tab can provide comprehensive drug abuse deterrence, resisting aqueous/organic solvent extraction, injection, and crisping, while retaining its therapeutic effect upon regular usage.

Comparing the effects of decreasing prescription opioid shipments and the release of an abuse deterrent OxyContin formulation on opioid overdose fatalities in WV: an interrupted time series study.

INTRODUCTION: The 2010 release of an abuse deterrent formulation (ADF) of OxyContin, a brand name prescription opioid, has been cited as a major driver for the reduction in prescription drug misuse and the associated increasing illicit opioid use and overdose rates. However, studies of this topic often do not account for changes in supplies of other prescription opioids that were widely prescribed before and after the ADF OxyContin release, including generic oxycodone formulations and hydrocodone. We therefore sought to compare the impact of the ADF OxyContin release to that of decreasing prescription opioid supplies in West Virginia (WV). METHODS: Opioid tablet shipment and overdose data were extracted from The Washington Post ARCOS (2006-2014) and the WV Forensic Drug Database (2005-2020), respectively. Locally estimated scatterplot smoothing (LOESS) was used to estimate the point when shipments of prescription opioids to WV began decreasing, measured via dosage units and morphine milligram equivalents (MMEs). Interrupted time series analysis (ITSA) was used to compare the impact LOESS-identified prescription supply changes and the ADF OxyContin release had on prescription (oxycodone and hydrocodone) and illicit (heroin, fentanyl, and fentanyl analogues) opioid overdose deaths in WV. Model fit was compared using Akaike Information Criteria (AIC). RESULTS: The majority of opioid tablets shipped to WV from 2006 to 2014 were generic oxycodone or hydrocodone, not OxyContin. After accounting for a 6-month lag from ITSA models using the LOESS-identified change in prescription opioid shipments measured via dosage units (2011 Q3) resulted in the lowest AIC for both prescription (AIC = -188.6) and illicit opioid-involved overdoses (AIC = -189.4), indicating this intervention start date resulted in the preferred model. The second lowest AIC was for models using the ADF OxyContin release as an intervention start date. DISCUSSION: We found that illicit opioid overdoses in WV began increasing closer to when prescription opioid shipments to the state began decreasing, not when the ADF OxyContin release occurred. Similarly, the majority of opioid tablets shipped to the state for 2006-2014 were generic oxycodone or hydrocodone. This may indicate that diminishing prescription supplies had a larger impact on opioid overdose patterns than the ADF OxyContin release in WV.

In vitro test methods for evaluating high molecular weight polyethylene oxide polymer induced hemolytic and thrombotic potential.

To combat opioid abuse, the U.S. Food and Drug Administration (FDA) released a comprehensive action plan to address opioid addiction, abuse, and overdose that included increasing the prevalence of abuse-deterrent formulations (ADFs) in opioid tablets. Polyethylene oxide (PEO) has been widely used as an excipient to deter abuse via nasal insufflation. However, changes in abuse patterns have led to unexpected shifts in abuse from the nasal route to intravenous injection. Case reports identify adverse effects similar to thrombotic thrombocytopenic purpura (TTP) syndrome following the intravenous (IV) abuse of opioids containing PEO excipient. Increased risk of IV opioid ADF abuse compared to clinical benefit of the drug led to the removal of one opioid product from the market in 2017. Because many generic drugs containing PEO are still in development, there is interest in assessing safety consistent with generic drug regulation and unintended uses. Currently, there are no guidelines or in vitro assessment tools to characterize the safety of PEO excipients taken via intravenous injection. To create a more robust excipient safety evaluation tool and to study the mechanistic basis of HMW PEO-induced TMA, a dynamic in vitro test system involving blood flow through a needle model has been developed.

Understanding syringeability and injectability of high molecular weight PEO solution through time-dependent force-distance profiles.

Opioid medications play a vital role in treating moderate to severe pain. Unfortunately, many drug misusers and abusers attempt to alter the formulations or properties of these drugs by manipulation, (e.g., crushing, chewing, smoking, snorting, injecting). The intravenous (IV) route is most dangerous to abusers, as the drugs directly enter the circulatory system and produce intense euphoria. To obtain a full understanding of the impact of syringe factors (e.g., needle gauge size, needle length, syringe barrel size), on the ease of injection, we undertook a comprehensive assessment of syringeability and injectability of manipulated abuse-deterrent formulations (ADFs). A texture analyzer-based testing method was developed for the measurement of the resistance force of pulling, holding, and pushing phases of injections. Results showed that the finer needle gauge sizes required higher injection force to withdraw drug solutions. In addition, the syringed liquid volume was highly dependent on needle gauge size, holding time, and sample viscosity. In most cases, a lower needle gauge number and a longer holding time increased the syringed volume. Needle length was highly correlated to injection force (R2 = 0.99). Using longer needles to inject drug solution requires greater force. Furthermore, large barrel size was correlated to pushing force (R2 = 0.99); thus, increasing the difficulty of pushing the plunger of a large syringe with one hand. Finally, relationships between injection force, sample viscosity, and testing conditions were elucidated using a mathematical model, which could be used in the future to assess and predict injection force of solution samples.

Asymmetrical Flow Field Flow Fractionation for Molar Mass Characterization of Polyethylene Oxide in Abuse-Deterrent Formulations.

High molar mass polyethylene oxide (HM-PEO) is commonly used to enhance the mechanical strength of solid oral opioid drug products to deter abuse. Because the properties of PEO depend on molar mass distribution, accurately determining the molar mass distribution is a necessary part of understanding PEO's role in abuse-deterrent formulations (ADF). In this study, an asymmetrical flow field-flow fractionation (AF4) analytical procedure was developed to characterize PEO polymers with nominal molar masses of 1, 4 or 7 MDa as well as those from in-house prepared placebo ADF. The placebo ADF were manufactured using direct compress or hot-melt-extrusion methods, and subjected to physical manipulation, such as heating and grinding before measurement by AF4 were performed. The molar mass distribution characterized by AF4 revealed that PEO was sensitive to thermal stress, exhibiting decreased molar mass with increased heat exposure. The optimized AF4 method was deemed suitable for characterizing HM-PEO, offering adequate dynamic separation range for PEO with molar mass from 100 kDa to approximately 10 MDa.

PLA-PCL microsphere formulation to deter abuse of prescription opioids by smoking.

Opioids are commonly prescribed across the United States (US) for pain relief, despite their highly addictive nature that often leads to abuse and overdose deaths. Abuse deterrent formulations (ADFs) for prescription opioids make the non-therapeutic use of these drugs more difficult and less satisfying. Although approximately one-third of surveyed abusers in the US reported smoking opioids, to our knowledge, no commercialized ADF effectively prevents opioid smoking. Here, we report a novel approach to deter smoking of a model prescription opioid drug, thebaine (THB), by using polymer blend microspheres (MS) comprising polylactic acid (PLA) and polycaprolactone (PCL). We utilized high-performance liquid chromatography (HPLC) and thermogravimetric analysis (TGA) to test the ability of PLA-PCL MS to limit the escape of vaporized THB. Additionally, we compared the abuse-deterrent potential of PLA-PCL MS to that of activated carbon (AC) and mesoporous silica (MPS), two materials with excellent drug-adsorbing properties. Our MS formulation was effective in reducing the amount of both active drug and thermal degradation products in the vapor generated upon heating of THB. These results support that PLA-PCL microspheres can be co-formulated in a tablet with common prescription opioids to deter their abuse via the smoking route.

Aversion liquid-filled drug releasing capsule (3D-RECAL): A novel technology for the development of immediate release abuse deterrent formulations using a fused deposition modelling (FDM) 3D printer.

COVID19 has caused a significant socioeconomic burden worldwide. Opioid crisis was further intensified with the increasing number of opioid overdose/misuse related deaths in last two years. Abusers have adopted newer/efficient methods for manipulating and abusing commercial opioid formulations. Food and Drug Administration (FDA) has been strategizing tirelessly to prevent misuse/abuse of prescription opioids. One of the strategies is to develop an abuse deterrent formulation (ADF). The current study aims to develop a novel 3D printed drug-releasing capsule shell filled with an aversion liquid (3D-RECAL). Primarily, metformin hydrochloride (MT, model drug) loaded printable filaments of polyvinyl alcohol was prepared using hot melt extrusion. Following extrusion, a 3D printed capsule shell was designed and fabricated using a single nozzle fuse deposition modelling 3D printer. An aversion liquid to be filled in 3D-RECAL capsules was prepared by combining sudan black and sodium polyacrylamide starch in oil base. Mechanical analysis of extruded filaments suggested that the filaments with 20%w/w MT had a higher mechanical strength compared to other drug loadings. Instantaneous gelling and large black non-snortable particles were formed during solvent extraction and physical manipulation studies, respectively. Due to the drug being embedded in the capsule shell, MT release was immediately started with >85% of MT release within 45 mins in 0.1 N HCl. Due to the everlasting need for the newer efficient ADF technologies, 3D-RECAL can be a step in the right direction towards saving lives, providing safe and effective measures to deterring abusers.

Evaluation of tableting performance of Poly (ethylene oxide) in abuse-deterrent formulations using compaction simulation studies.

Poly (ethylene oxide) (PEO) has been widely used in abuse-deterrent formulations (ADFs) to increase tablet hardness. Previous studies have shown that formulation variables such as processing conditions and particle size of PEO can affect ADF performance in drug extraction efficiency. This work aims to understand the effect of PEO grades and sources on the compaction characteristics of model ADFs. PEOs from Dow Chemical and Sumitomo Chemical with different molecular weights were examined using a Styl'One compaction simulator at slow, medium, and fast tableting speeds. Particle-size distribution, thermal behavior, tabletability, compressibility using the Heckel model, compactibility, and elastic recovery were determined and compared between the neat PEOs and model ADFs. Multivariate linear regression was performed to understand the effect of compression conditions and PEO grades and sources. Our results show that neat PEOs with high molecular weight exhibit high tabletability. The source of neat PEOs contributes to the difference in tabletability, out-die compressibility, compactibility, and elastic recovery. However, the influence of the PEO source on tabletability and compactibility decreases after adding the model drug. In our model ADFs, tablets using PEOs with high molecular weight have high crushing strength, and tablets using PEOs from Dow Chemical display low elastic recovery.