Driven by increasing opioid addiction, drug overdose has become a leading cause of death in the United States [1]. The disruption of daily life, isolation, and anxiety due to the COVID-19 pandemic have only compounded the problem [2]. Opioids are highly effective analgesics if taken as prescribed. However, individuals struggling with drug addiction may alter the method of ingestion, which can result in a rapid increase in the drug concentration in the blood, often leading to fatal consequences. Alternative methods of ingestion include crushing tablets to create a powder for insufflation, smoking, or further processing for injection. The drug in powder form can readily be extracted by common household solvents, such as ethanol, vinegar, or carbonated drinks.

Pharmaceutical companies have tried to balance the benefits and risks of opioid therapy by developing various abuse-deterrent formulations (ADFs) [3]. ADFs are special dosage forms designed to discourage physical and chemical tampering of the formulation without losing the therapeutic effects of opioids. Most ADFs rely on polymer excipients that have thermal, gelling, swelling, mechanical, binding, or film-forming properties [4], thereby limiting the isolation of the drug from the tablet. For example, ADFs utilize polymers such as high molecular weight polyethylene oxide (PEO) that form viscous gels upon contact with water, deterring both intravenous injection and extraction [5,6]. Other formulations make tablets difficult to crush. Alternatively, agonist/antagonist combinations [7] or aversive agents [8] are included as pharmacological deterrents to offset the effect of the opioid if manipulated by abusers.

ADFs have proven effective in decreasing the rate of prescription opioid abuse by 75% [9]. However, abusers have also developed more complex extraction strategies to circumvent the ADF technologies. For example, special polymers are used to form viscous solutions or swollen gels in water, making them difficult to inject. Abusers may overcome this approach by heating ADFs with a candle, lighter, or microwave to destroy the polymers (an approach called crisping) and interfere with gelling or swelling to afford a chance to extract the drug [10]. Moreover, abusers can exploit the fact that those polymers may not prevent drug extraction by organic solvents such as ethanol or acetone. They may put extended-release tablets in vodka and then drink the solution at once. Abusers may also extract the drug using a volatile organic solvent, evaporate the solvent after filtering the undissolved polymer, and reconstitute the extracted drug in water to inject. Abusers also manipulate the pH and salt contents of the solution to affect the gelling properties of polymers. These techniques are posted online and made freely available to the public [11]. Therefore, there is a strong need for new technologies to overcome the limitations of current ADFs.

In this study, we aim to develop a comprehensive ADF tablet, which prevents aqueous/organic solvent extraction, injection, and crisping but provides necessary analgesia if taken as prescribed. To this end, we design a new ADF approach based on a hybrid of nanoparticles (NPs) and gel-forming polymers, wherein each component deters drug abuse via distinct mechanisms. First, we encapsulate a model opioid compound, thebaine, in iron-crosslinked tannic acid NPs, which serve as a chemical barrier to drug extraction by organic solvents such as ethanol and acetone. The NPs are then combined with polymers used in marketed ADF products to make a tablet, which forms a gel in aqueous solutions to interfere with injection. Herein, we describe the development of a new ADF tablet formulation consisting of organic solvent-proof NPs and gel-forming polymers. We also evaluate the performance of the components and the final tablet product subject to common “abuse protocols,” including solution preparation, solvent extraction, and crisping.