(T1130-01-04) Novel Abuse-Deterrent Tablet to Combat Opioid Abuse: A Hot Melt Extrusion Approach

Purpose: Drug abusers often resort to snorting, extracting, or injecting medications for a faster, more intense effect. This study addresses these abuse methods by evaluating abuse-deterrent formulations The major aim of this study was to develop and assess abuse-deterrent tablet formulations using hot melt extrusion, with acetaminophen as a model drug (1). It further examines the impact of various excipients, and various manipulations (physical, chemical, and thermal) on drug release from these tablet dosage forms. The overall goal is to create formulations resistant to tampering or misuse, while preserving therapeutic effectiveness, offering a potential approach for developing abuse-deterrent solid dosage forms (2,3).

Methods: A custom grid design of experiments approach, utilizing R programming language, was implemented to generate 16 formulations (F1, F2,…..F16) with diverse compositions of polyethylene oxide, polyvinylpyrrolidone/ vinyl acetate copolymer, hydroxypropyl methylcellulose, stearic acid, and polyethylene glycol 8000. Drug extraction studies evaluated the resistance of the formulation to tampering in various solvents, including shaking with 0.1N HCL, 0.1N NaOH, 40% Ethanol, 96% Ethanol, and Isopropyl Alcohol at 500 RPM for 30 minutes, and microwaving with water at 1500 W for 1 minute. A 40% cutoff limit was established and formulations F2, F5, and F10 were selected with extraction (%) less than this limit. Tablet hardness was evaluated using an MTS Insight Electromechanical test frame and compared with control (non-abuse deterrent formulation). Particle size reduction analysis was performed after grinding tablets in a coffee grinder for 30 seconds and sieving through a 150-micron mesh. Gel formation assessments involved exposing tablets to water at 500 RPM and visually examining the extent of gel formation. Moisture uptake studies employed a vacuum desiccator with saturated solutions of MgSO₄·6H₂O (30% RH), NaI (50% RH), and (NH₄)₂SO₄ (75% RH), monitoring tablet weight until no further change was detected. In vitro release studies were carried out using a USP apparatus 2 (paddle) at 37°C and 50 RPM for 8 hours in simulated gastric fluid (pH 1.2) and intestinal fluid (pH 6.8) conditions. Thermal analyses, including Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA), were performed on formulations and individual components by heating samples from 30°C to 300°C at a 10°C/min ramp rate. Tablet surface morphology was investigated using Scanning Electron Microscopy (SEM) to compare and analyze surface alterations in intact, physically manipulated, and thermally manipulated tablets. The formulations were optimized to enhance gel viscosity and improve extended-release properties. These optimized formulations were further examined for thermal analyses, tablet surface morphology, in vitro release, particle size reduction, gel formation, and drug extraction properties in various solvents.

Results: This comprehensive evaluation of abuse-deterrent characteristics provides a foundation for developing robust formulations to counteract the growing issue of prescription drug abuse. The study focuses on understanding the implications of the experimental results in terms of abuse-deterrence and optimizing formulations to ensure they are resistant to tampering while maintaining controlled drug release. It was also found that the formulations exhibited sustained drug release properties with approximately 50-60% drug release in 8 hours. The optimized F2 and F5 tablets had minimal deformation upon physical and thermal manipulation and showed drug release profiles that correlated with their physical properties. In contrast, the optimized F10 tablets showed cracks on their surface upon manipulation and maintained sustained release characteristic. The moisture uptake studies showed that the optimized F2, F5, and F10 had weight gains of less than 2% at RH levels of 30% and 50%. However, at RH 75%, the weight gain was between 7-12%. Moreover, the optimized formulations showed rapid gel formation, the particle size reduction studies showed that < 0.01% particles passed through 150-micron mesh as compared to 40% in case of control (non- abuse deterrent formulation), and the drug extraction in different solvents was less than 40% (except for optimized F10, which showed more than 40% extraction in case of 0.1N NaOH and 96% Ethanol).

Conclusion: This study highlights the effectiveness of the hot melt extrusion technique, coupled with a design approach, for formulating abuse-deterrent tablets with sustained drug release properties. The study's findings demonstrate that the selected optimized formulations (F2 and F5) exhibited prolonged drug release, maintained physical and thermal stability, and have the potential for developing abuse-deterrent tablets for acetaminophen. These results provide a foundation for developing abuse-deterrent formulations for other drugs, which can help combat drug abuse and reduce its incidence. The optimized formulations, coupled with the study's comprehensive evaluation of abuse-deterrent characteristics, offer a promising approach for addressing the opioid epidemic and other drug-related public health concerns.

References: 1) Butreddy, Arun, Dinesh Nyavanandi, Sagar Narala, Fischer Austin, and Suresh Bandari. "Application of Hot Melt Extrusion Technology in the Development of Abuse-Deterrent Formulations: An Overview." Current Drug Delivery 18, no. 1 (2021): 4-18. https://doi.org/10.2174/1567201817999200817151601. PMID: 32811398
2) Simon, K., Worthy, S. L., Barnes, M. C., & Tarbell, B. (2015). Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety. Therapeutic Advances in Drug Safety, 6(2), 67–79. https://doi.org/10.1177/2042098615569726. PMID: 25922655; PMCID: PMC4406920.
3) JEC Analysis Finds Opioid Epidemic Cost U.S. Nearly $1.5 Trillion in 2020. Retrieved from https://www.jec.senate.gov/public/index.cfm/democrats/2022/9/jec-analysis-finds-opioid-epidemic-cost-u-s-nearly-1-5-trillion-in-2020

Acknowledgements: The authors thank Dr. Joel Destino, Assistant Professor, College of Arts and Sciences, Creighton University, for SEM imaging, and Dr. Mark A. Latta, Professor, School of Dentistry, Creighton University for hardness testing.

Funding: The authors gratefully thank the Department of Pharmacy Sciences, Creighton University, for the financial support. Conflict of Interest Statements: We confirm that there are no conflicts of interest associated with this work, and there has been no significant financial support for this work that could have influenced its outcome.

Drug extraction studies for the optimized F2, F5, and F10 formulations in different solvent conditions

Tablet physical studies for the formulations and control (non-abuse deterrent formulation)

In vitro release studies for the optimized F2, F5, and F10 formulations (intact, physically manipulated, and thermally manipulated) in gastric pH 1.2 (top) and in intestinal pH 6.8 (bottom) at 37 ± 0.2°C