(M1430-05-29) Addressing the Opioid Crisis: Assessing Abuse-Deterrent Formulations Utilizing Ion-Exchange Resin Complexation Processed via Twin-Screw Granulation for Improved Safety and Effectiveness

Purpose: Opioids, commonly prescribed for chronic pain, have led to increased usage but also a rise in drug abuse, especially with extended-release formulations. Misuse, either intentional or unintentional, can result in lethal outcomes and/or unwanted side effects. Abusers are attracted to extended-release formulations due to their high amount of active opioids, inducing a strong euphoric effect. The combination of alcohol and opioids can lead to alcohol-induced dose dumping. To address these issues, there's a shift towards developing Abuse Deterrent Formulations (ADFs) to deter opioid abuse. Regulatory agencies and pharmaceutical firms focus on creating ADFs, with matrix tablets being a common form. However, there is significant interest in developing new technologies to impede the misuse of medications, and one such technology involves Ion-Exchange Resin (IER) complexes.

Methods: The Drug-Resin Complex (DRC) was prepared using Twin-Screw Wet Granulation (TSWG) with an 11mm twin-screw extruder (Process 11™, Thermo Fisher Scientific, TX, USA). The stoichiometric ratio of Promethazine hydrochloride (PMZ) and Ion-Exchange Resin (IER) was fixed at 1:2 based on complexation efficiency studies.  As neither material is thermoplastic, water was used to aid complexation in HME. The thick suspension obtained from HME was collected, dried at 60°C for 12 hours, sieved through US Mesh #50, and stored. The dried material served as the starting material for DRC-polymer granules. Two polymer sets were investigated as mentioned in Figure 1. Barrel temperatures were adjusted for different polymers, with 95°C for Kollicoat SR and Kollicoat MAE 100P, and 160°C for HPMC and HPMC-AS. The screw speed remained constant at 50 RPM. Granules obtained after Twin-Screw Melt Granulation (TSMG) were milled, sieved, and compressed into tablets.

Results: Dissolution: Formulations F4 to F9, containing 80 mg equivalent of PMZ, underwent dissolution studies using acid and buffer stage dissolution media. The USP-2 apparatus (Paddle) at 50RPM was used. Acid stage dissolution occurred in 750 mL of pH 1.2 HCl buffer, followed by the addition of 250 mL of 0.45M dibasic potassium phosphate solution at 2hrs, adjusting the pH to 6.8. Formulation F7 achieved the targeted release profile of ≥85% between 12 to 18 hrs (82.65% at 12hrs, 90.17% at 18hrs) as depicted in Figure 2. F7 was chosen as the optimized formulation for further studies due  to its desired release profile. Abuse deterrent studies: Solvent extraction studies; To assess the abuse deterrence of the formulation, solvents recommended by the FDA, were chosen for extraction. The results depicted in Figure 3A showed that none of the solvents could extract over 30% of the drug even after 12 hours (except for Ethanol ~50% & 0.2% baking soda ~30%). This indicates the efficiency of the formulation to effectively hinder PMZ release from extraction by various solvents. Dissolution studies of intact and grounded tablets: The impact of tablet grounding on the dissolution profile of PMZ-loaded tablets is depicted in the accompanying Figure 3B. Grounding the tablet significantly accelerated the release of PMZ due to the increased surface area of contact. Specifically at the end of the first 0.5hours, the grounded tablet released ~35%, whereas the intact tablet released ~5%. Beyond this initial burst release, the grounded tablet demonstrated a sustained release pattern at subsequent time points. It took approximately 3 hours to release more than 50% of PMZ. Like intact tablets, grounded tablets also took 12 hours to release ~85%. Dose dumping studies: Figure-3C depicts the cumulative release of PMZ in two dissolution media: 0.1N HCl and 0.1N HCl with 40% ethanol. The presence of alcohol significantly influences drug release, particularly in the initial stages, where release is accelerated. However, after 120 minutes, release plateaued at approximately 25% in both media. The similarity factor (f2) was found to be 52, suggesting the formulation effectively mitigates dose dumping in the presence of alcohols.

Conclusion: The FDA actively advocates for the development of Abuse-Deterrent Formulations (ADFs) as a crucial strategy to combat opioid abuse. While these formulations may not provide absolute abuse resistance, the FDA believes they play a pivotal role in reducing opioid abuse. Our study highlights the potential of Ion-Exchange Resin (IER) as a promising chemical barrier system for ADFs. Smoking abuse is prevented by the complexation of PMZ with IER, hindering drug release upon heating. For snorting or injection abuse, drug extraction from the complex is necessary, posing challenges due to the larger size of complexed particles. In FDA-recommended solvents, drug extraction didn't exceed 25% after 12 hours, except for a 0.2% baking soda solution (~30%) and ethanol (~60%). Dissolution tests and a comparison between ground and intact tablets demonstrated extended-release behavior, with consistent ≥85% release at 12 hours. Maintaining abuse-deterrent properties, even in the presence of alcohol, is crucial, and alcohol dose dumping studies confirmed effective mitigation following FDA guidelines in the presence of 40% EtOH.

References: Siva Ram Munnangi, Nagarjuna Narala, Preethi Lakkala, Sateesh Kumar Vemula, Michael Repka, Assessing Abuse-Deterrent formulations utilizing Ion-Exchange resin complexation processed via Twin-Screw granulation for improved safety and effectiveness, European Journal of Pharmaceutics and Biopharmaceutics, Volume 197, 2024, 114230, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114230.

Acknowledgements: We would like to acknowledge Purolite®, Ashland™ and BASF for kindly gifting the required materials for the project.

Funding: This research did not receive any specific grants from funding agencies in the public, commercial or not-from-profit sectors.


Figure 1: Compositions of all the formulations investigated in this study.


Figure 2: Drug dissolution profiles of different formulations.


Figure 3: 3A - Drug extraction in presence of different solvent over a period of 12 hrs; 3B - Drug dissolution studies of grounded and intact tablets of F7 formulation; 3C - Drug dissolution profiles of the F7 formulation tablets, in the presence and absence of alcohol.