Abuse Deterrent Dosage Forms: Approaches, Advantages and Limitations

Haneen Talal Mohammad; Thamer Abduljabbar Omar

doi:10.54133/ajms.v7i2.1277

Authors

Haneen Talal Mohammad Department of Pharmaceutics, College of Pharmacy, University of Mosul, Mosul, Iraq https://orcid.org/0009-0000-9072-654X
Thamer Abduljabbar Omar Department of Pharmaceutics, College of Pharmacy, University of Mosul, Mosul, Iraq https://orcid.org/0000-0002-7523-0850

DOI:

https://doi.org/10.54133/ajms.v7i2.1277

Keywords:

Abuse deterrent formulations, Abuse deterrent technology, Aversive agent, Drug abuse, Polyethylene oxide

Abstract

Background: Abuse-deterrent formulations (ADFs) are dosage forms designed to prevent or discourage the misuse of prescription drugs, particularly opioids. They achieve this aim by either minimizing the benefit of tampering with the dosage form or making it challenging to change this dosage form. Therefore, one of the priorities for public health is to develop dosage forms that have abuse-deterrent formulations. The escalation in the prescription of opioids has led to a surge in their abuse or misuse, resulting in a high mortality rate. Objectives: This review article explores drug abuse methods among addicted individuals and lists the most frequently abused drug classes. Furthermore, this review concentrates on understanding the most prevalent technologies used to deter abuse of prescribed opioid drugs. Methods: The search included online published databases from PubMed, Google Scholar, Research Gate, Science Direct, Elsevier, and others. The objective was to collect as much information as possible from articles using the keywords “abuse deterrent formulations and abuse deterrent technology." Conclusions: Physical-chemical barriers and agonist-antagonist formulations are available as marketed drugs as well as aversive agents’ formulations. Each of these types can inhibit or reduce specific cases of opioid misuse. Although the success of these products mostly relies on robust formulation strategies, it also requires a thorough understanding of their benefits and broad adoption in the market.

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References

Gad SC, (Ed.), Pharaceutical Manufacturing Handbook, John Wiley & Sons, Inc.; 2008. 1386 p.

Gaikwad SS, Kshirsagar SJ. Review on Tablet in Tablet techniques. Beni-Suef Univ J Basic Appl Sci. 2020;9:1-7. doi: 10.1186/s43088-019-0027-7. DOI: https://doi.org/10.1186/s43088-019-0027-7

Hedaya M, Aldeeb D. The need for tamper-resistant and abuse-deterrent formulations. J Pharma Care Health Syst. 2014;1(1). doi: 10.4172/2376-0419.1000e102. DOI: https://doi.org/10.4172/2376-0419.1000e102

Mastropietro DJ, Omidian H. Current approaches in tamper-resistant and abuse-deterrent formulations. Drug Dev Ind Pharm. 2013;39(5):611-624. DOI: https://doi.org/10.3109/03639045.2012.680468

Lessenger JE, Feinberg SD. Abuse of prescription and over-the-counter medications. J Am Board Fam Med. 2008;21(1):45-54. doi: 10.3122/jabfm.2008.01.070071. DOI: https://doi.org/10.3122/jabfm.2008.01.070071

Altomare C, Kinzler ER, Buchhalter AR, Cone EJ, Costantino A. Laboratory-based testing to evaluate abuse-deterrent formulations and satisfy the Food and Drug Administration's recommendation for Category 1 Testing. J Opioid Manag. 2017;13(6):441-448. doi: 10.5055/jom.2017.0420. DOI: https://doi.org/10.5055/jom.2017.0420

Palekar S, Nukala PK, Vartak R, Patel K. Abuse deterrent immediate release film technology (ADRIFT): A novel bilayer film technology for limiting intentional drug abuse. Int J Pharm. 2020;590:119944. doi: 10.1016/j.ijpharm.2020.119944. DOI: https://doi.org/10.1016/j.ijpharm.2020.119944

Jones CM. Reprint of trends and key correlates of prescription opioid injection misuse in the United States. Addict Behav. 2018;86:24-31. doi: 10.1016/j.addbeh.2018.07.008. DOI: https://doi.org/10.1016/j.addbeh.2018.07.008

Barakh Ali SF, Dharani S, Afrooz H, Mohamed EM, Cook P, Khan MA, et al. Development of abuse-deterrent formulations using sucrose acetate isobutyrate. AAPS PharmSciTech. 2020;21(3):99. doi: 10.1208/s12249-020-01646-8. DOI: https://doi.org/10.1208/s12249-020-01646-8

Gadd S, Cox N, Samuelson J, Kenney A, Turner K, Cochran G. Abuse-deterrent opioid formulations and the opioid crisis: a pharmacist's perspective. Ther Drug Monit. 2021;43(1):35-41. doi: 10.1097/FTD.0000000000000844. DOI: https://doi.org/10.1097/FTD.0000000000000844

Pon D, Awuah K, Curi D, Okyere E, Stern CS. Combating an epidemic of prescription opioid abuse. J Calif Dent Assoc. 2015;43(11):673-678. doi: 10.1080/19424396.2015.12222919. DOI: https://doi.org/10.1080/19424396.2015.12222919

Meruva S, Donovan MD. Polyethylene oxide (PEO) molecular weight effects on abuse-deterrent properties of matrix tablets. AAPS PharmSciTech. 2019;21(1):28. doi: 10.1208/s12249-019-1565-y. DOI: https://doi.org/10.1208/s12249-019-1565-y

Rudd RA. Increases in drug and opioid-involved overdose deaths—United States, 2010–2015. Morb Mortal Wkly Rep. 2016;65. DOI: https://doi.org/10.15585/mmwr.mm655051e1

Bannwarth B. Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose? Drugs. 2012;72(13):1713-1723. doi: 10.2165/11635860-000000000-00000. DOI: https://doi.org/10.2165/11635860-000000000-00000

Morone NE, Weiner DK. Pain as the fifth vital sign: exposing the vital need for pain education. Clin Ther. 2013;35(11):1728-1732. doi: 10.1016/j.clinthera.2013.10.001. DOI: https://doi.org/10.1016/j.clinthera.2013.10.001

Smith SM, Dart RC, Katz NP, Paillard F, Adams EH, Comer SD, et al. Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. Pain. 2013;154(11):2287-2296. doi: 10.1016/j.pain.2013.05.053. DOI: https://doi.org/10.1016/j.pain.2013.05.053

Gasior M, Bond M, Malamut R. Routes of abuse of prescription opioid analgesics: a review and assessment of the potential impact of abuse-deterrent formulations. Postgrad Med. 2016;128(1):85-96. doi: 10.1080/00325481.2016.1120642. DOI: https://doi.org/10.1080/00325481.2016.1120642

Grady D, Berkowitz SA, Katz MH. Opioids for chronic pain. Arch Intern Med. 2011;171(16):1426-1427. doi: 10.1001/archinternmed.2011.213. DOI: https://doi.org/10.1001/archinternmed.2011.213

Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician. 2010;13(5):401. DOI: https://doi.org/10.36076/ppj.2010/13/401

Nicholson B. Responsible prescribing of opioids for the management of chronic pain. Drugs. 2003;63(1):17-32. doi: 10.2165/00003495-200363010-00002. DOI: https://doi.org/10.2165/00003495-200363010-00002

Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med. 2010;363(21):1981-1985. doi: 10.1056/NEJMp1011512. DOI: https://doi.org/10.1056/NEJMp1011512

Woodcock J. A difficult balance — Pain management, drug safety, and the FDA. N Engl J Med. 2009;361(22):2105-2107. doi: 10.1056/NEJMp0908913. DOI: https://doi.org/10.1056/NEJMp0908913

Pergolizzi JV, Raffa RB, Taylor R, Vacalis S. Abuse-deterrent opioids: an update on current approaches and considerations. Curr Med Res Opin. 2018;34(4):711-723. DOI: https://doi.org/10.1080/03007995.2017.1419171

Alexander L, Weingarten B. A pharmacist’s guide to the emerging abuse deterrence technology used in opioid analgesics. Evaluation. 2013;5.

Compton WM, Volkow ND. Abuse of prescription drugs and the risk of addiction. Drug Alcohol Depend. 2006;83:S4-S7. doi: 10.1016/j.drugalcdep.2005.10.020. DOI: https://doi.org/10.1016/j.drugalcdep.2005.10.020

Dixit MA, Pawar V, Patel R, Patel M. Abuse deterrent soft chewable drug formulations. Google Patents; 2019.

Katz N, Dart RC, Bailey E, Trudeau J, Osgood E, Paillard F. Tampering with prescription opioids: Nature and extent of the problem, health consequences, and solutions. Am J Drug Alcohol Abuse. 2011;37(4):205-217. doi: 10.3109/00952990.2011.569623. DOI: https://doi.org/10.3109/00952990.2011.569623

Califf RM, Woodcock J, Ostroff S. A proactive response to prescription opioid abuse. N Engl J Med. 2016;374(15):1480-1485. doi: 10.1056/NEJMsr1601307. DOI: https://doi.org/10.1056/NEJMsr1601307

Omidian A, Mastropietro D, Omidian H. Reported methods of abuse for common prescription analgesic opioids. J Dev Drugs. 2013;3(02):1-3. DOI: https://doi.org/10.4172/2329-6631.1000120

Nguyen V, Raffa R, Taylor R, Pergolizzi J. The role of abuse‐deterrent formulations in countering opioid misuse and abuse. J Clin Pharm Ther. 2015;40(6):629-634. doi: 10.1111/jcpt.12337. DOI: https://doi.org/10.1111/jcpt.12337

Mastropietro DJ, Omidian H. Abuse-deterrent formulations: part 1 – development of a formulation-based classification system. Expert Opin Drug Metab Toxicol. 2015;11(2):193-204. doi: 10.1517/17425255.2015.979786.

Vora LK, Gholap AD, Jetha K, Thakur RRS, Solanki HK, Chavda VP. Artificial intelligence in pharmaceutical technology and drug delivery design. Pharmaceutics. 2023;15(7):1916. doi: 10.3390/pharmaceutics15071916. DOI: https://doi.org/10.3390/pharmaceutics15071916

Moorman-Li R, Motycka CA, Inge LD, Congdon JM, Hobson S, Pokropski B. A review of abuse-deterrent opioids for chronic nonmalignant pain. P & T. 2012;37(7):412.

Manipriyanka K, Naidu RK. Advances in drug formulation technology: Enhancing bioavailability and patient compliance. J Adv Zool. 2023;44. doi: 10.17762/jaz.v44iS-5.1719. DOI: https://doi.org/10.17762/jaz.v44iS-5.1719

Hout SA. Manufacturing of quality oral drug products: Processing and safe handling of active pharmaceutical ingredients (API): CRC Press; 2022. DOI: https://doi.org/10.1201/9781003224716

Al-Dulaimi AF, Al-kotaji M, Abachi FT. Development of novel paracetamol/naproxen co-crystals for improvement in naproxen solubility. Iraqi J Pharm Sci. 2022;31(1):202-219. doi: 10.31351/vol31iss1pp202-219. DOI: https://doi.org/10.31351/vol31iss1pp202-219

Abrantes CG, Duarte D, Reis CP. An overview of pharmaceutical excipients: safe or not safe? J Pharm Sci. 2016;105(7):2019-2026. doi: 10.1016/j.xphs.2016.03.019. DOI: https://doi.org/10.1016/j.xphs.2016.03.019

Ya-Han L, Brown DL, Hsiang-Yin C. Current impact and application of abuse-deterrent opioid formulations in clinical practice. Pain Physician. 2017;20(7):E1003. DOI: https://doi.org/10.36076/ppj/2017.7.E1003

Mayock SP, Saim S, Fleming AB. In vitro drug release after crushing: evaluation of Xtampza® ER and other ER opioid formulations. Clin Drug Investig. 2017;37:1117-1124. doi: 10.1007/s40261-017-0561-9. DOI: https://doi.org/10.1007/s40261-017-0561-9

Webster LR, Markman J, Cone EJ, Niebler G. Current and future development of extended-release, abuse-deterrent opioid formulations in the United States. Postgrad Med. 2017;129(1):102-110. DOI: https://doi.org/10.1080/00325481.2017.1268902

Habib WA, Hamed E, Zepeda MAV. Abuse resistant drug formulation. United States patent US 8,445,018; 2013.

Litman RS, Pagán OH, Cicero TJ. Abuse-deterrent opioid formulations. Anesthesiology. 2018;128(5):1015-1026. doi: 10.1097/aln.0000000000002031. DOI: https://doi.org/10.1097/ALN.0000000000002031

Mastropietro DJ, Omidian H. Abuse-deterrent formulations: part 1–development of a formulation-based classification system. Expert Opin Drug Metab Toxicol. 2015;11(2):193-204. DOI: https://doi.org/10.1517/17425255.2015.979786

Herry C, Monti A, Vauzelle-Kervroedan F, Oury P, Michel L. Reducing abuse of orally administered prescription opioids using formulation technologies. J Drug Deliv Sci Technol. 2013;23(2):103-110. doi: 10.1016/S1773-2247(13)50017-7. DOI: https://doi.org/10.1016/S1773-2247(13)50017-7

Externbrink A, Sharan S, Sun D, Jiang W, Keire D, Xu X. An in vitro approach for evaluating the oral abuse deterrence of solid oral extended-release opioids with properties intended to deter abuse via chewing. Int J Pharm. 2019;561:305-313. doi: 10.1016/j.ijpharm.2019.03.017. DOI: https://doi.org/10.1016/j.ijpharm.2019.03.017

Babul N. Multimodal abuse resistant and extended release opioid formulations. Google Patents; 2015.

Guimberteau F, Dargelas F. Anti-misuse microparticulate oral pharmaceutical form. Google Patents; 2014.

Brzeczko AW. Pharmaceutical compositions for deterring misuse, abuse, and diversion. Google Patents; 2012.

Maincent J, Zhang F. Recent advances in abuse-deterrent technologies for the delivery of opioids. Int J Pharm. 2016;510(1):57-72. doi: 10.1016/j.ijpharm.2016.06.012. DOI: https://doi.org/10.1016/j.ijpharm.2016.06.012

Muppalaneni S, Mastropietro DJ, Omidian H. Crush resistance and insufflation potential of poly (ethylene oxide)-based abuse deterrent formulations. Expert Opin Drug Deliv. 2016;13(10):1375-1382.

Bartholomaeus JH, Arkenau-Marić E, Galia E. Opioid extended-release tablets with improved tamper-resistant properties. Expert Opin Drug Deliv. 2012;9(8):879-891. DOI: https://doi.org/10.1517/17425247.2012.698606

Cohen JP, Mendoza M, Roland C. Challenges involved in the development and delivery of abuse-deterrent formulations of opioid analgesics. Clin Ther. 2018;40(2):334-344. DOI: https://doi.org/10.1016/j.clinthera.2018.01.003

Stanos SP, Bruckenthal P, Barkin, RL. Strategies to reduce the tampering and subsequent abuse of long-acting opioids: Potential risks and benefits of formulations with physical or pharmacologic deterrents to tampering. Mayo Clin Proc. 2012;87(7):683-694. doi: 10.1016/j.mayocp.2012.02.022. DOI: https://doi.org/10.1016/j.mayocp.2012.02.022

Davis M, Goforth HW, Gamier P. Oxycodone combined with opioid receptor antagonists: efficacy and safety. Expert Opin Drug Saf. 2013;12(3):389-402. 10.1517/14740338.2013.783564. DOI: https://doi.org/10.1517/14740338.2013.783564

Raffa RB, Pergolizzi JV. Opioid formulations designed to resist/deter abuse. Drugs. 2010;70:1657-1675. DOI: https://doi.org/10.2165/11537940-000000000-00000

Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009;84(7):593-601. doi: 10.1016/s0025-6196(11)60748-9. DOI: https://doi.org/10.4065/84.7.593

Ruan X, Chen T, Gudin J, Couch JP, Chiravuri S. Acute opioid withdrawal precipitated by ingestion of crushed embeda (morphine extended release with sequestered naltrexone): case report and the focused review of the literature. J Opioid Manag. 2010;6(4):300-303. doi: 10.5055/jom.2010.0028. DOI: https://doi.org/10.5055/jom.2010.0028

Rana D, Salave S, Benival D. Emerging trends in abuse-deterrent formulations: technological insights and regulatory considerations. Curr Drug Deliv. 2022;19(8):846-859. doi: 10.2174/1567201818666211208101035. DOI: https://doi.org/10.2174/1567201818666211208101035

Schaeffer T. Abuse-deterrent formulations, an evolving technology against the abuse and misuse of opioid analgesics. J Med Toxicol. 2012;8(4):400-407. doi: 10.1007/s13181-012-0270-y. DOI: https://doi.org/10.1007/s13181-012-0270-y

Mastropietro DJ, Omidian H. Abuse-deterrent formulations: Part 2: commercial products and proprietary technologies. Expert Opin Pharmacother. 2015;16(3):305-323. doi: 10.1517/14656566.2014.970175. DOI: https://doi.org/10.1517/14656566.2014.970175

Oshlack B, Colucci R, Wright C, Breder C. Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent. Google Patents; 2006.

Riley AL, Manke HN, Huang S. Impact of the aversive effects of drugs on their use and abuse. Behav Neurol. 2022;2022:8634176. doi: 10.1155/2022/8634176. DOI: https://doi.org/10.1155/2022/8634176

Simon K, Worthy SL, Barnes MC, Tarbell B. Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety. Ther Adv Drug Saf. 2015;6(2):67-79. doi: 10.1177/2042098615569726. DOI: https://doi.org/10.1177/2042098615569726

Opioids A-D. Evaluation and labeling guidance for industry. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Clinical Medical. 2015.

Cassidy TA, McNaughton EC, Varughese S, Russo L, Zulueta M, Butler SF. Nonmedical use of prescription ADHD stimulant medications among adults in a substance abuse treatment population: early findings from the NAVIPPRO surveillance system. J Atten Disord. 2015;19(4):275-283. doi: 10.1177/108705471349332. DOI: https://doi.org/10.1177/1087054713493321

Cassidy TA, Varughese S, Russo L, Budman SH, Eaton TA, Butler SF. Nonmedical use and diversion of ADHD stimulants among US adults ages 18-49: a national internet survey. J Atten Disord. 2015;19(7):630-640. doi: 10.1177/10870547124684. DOI: https://doi.org/10.1177/1087054712468486

Sweeney CT, Sembower MA, Ertischek MD, Shiffman S, Schnoll SH. Nonmedical use of prescription ADHD stimulants and preexisting patterns of drug abuse. J Addict Dis. 2013;32(1):1-10. doi: 10.1080/10550887.2012.759858. DOI: https://doi.org/10.1080/10550887.2012.759858

Huttunen KM, Raunio H, Rautio J. Prodrugs—from serendipity to rational design. Pharmacol Rev. 2011;63(3):750-771. doi: 10.1124/pr.110.003459. DOI: https://doi.org/10.1124/pr.110.003459

Katz N. Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep. 2008;10(1):11-18. doi: 10.1007/s11926-008-0003-z. DOI: https://doi.org/10.1007/s11926-008-0003-z

Gudin JA, Nalamachu SR. An overview of prodrug technology and its application for developing abuse-deterrent opioids. Postgrad Med. 2016;128(1):97-105. doi: 10.1080/00325481.2016.1126186. DOI: https://doi.org/10.1080/00325481.2016.1126186

Hale ME, Moe D, Bond M, Gasior M, Malamut R. Abuse-deterrent formulations of prescription opioid analgesics in the management of chronic noncancer pain. Pain Manag. 2016;6(5):497-508. doi: 10.2217/pmt-2015-0005. DOI: https://doi.org/10.2217/pmt-2015-0005

Adler JA, Mallick-Searle T. An overview of abuse-deterrent opioids and recommendations for practical patient care. J Multidiscip Healthc. 2018;11:323-332. doi: 10.2147/JMDH.S166915. DOI: https://doi.org/10.2147/JMDH.S166915

Cicero TJ, Ellis MS, Kasper ZA. Relative preferences in the abuse of immediate‐release versus extended‐release opioids in a sample of treatment‐seeking opioid abusers. Pharmacoepidemiol Drug Saf. 2017;26(1):56-62. doi: 10.1002/pds.4078. DOI: https://doi.org/10.1002/pds.4078

Xtampza® ER label. (Accessed June 11, 2024). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208090s003lbl.pdf

Vantrela® ER label. (Accessed 11 June 2024). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207975s000lbl.pdf

Hysingla® ER label. (Accessed 11 June 2024). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206627s004lbl.pdf

Targiniq® ER label. (Accessed 11 June 2024). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205777lbl.pdf

Romach MK, Schoedel KA, Sellers EM. Update on tamper-resistant drug formulations. Drug Alcohol Depend. 2013;130(1):13-23. doi: 10.1016/j.drugalcdep.2012.12.028. DOI: https://doi.org/10.1016/j.drugalcdep.2012.12.028

Ahmad R, Omidian H. Development and in vitro evaluation of an abuse-deterrent formulation based on a crosslinked starch derivative. Int J Pharm. 2019;569:118602. doi: 10.1016/j.ijpharm.2019.118602. DOI: https://doi.org/10.1016/j.ijpharm.2019.118602

Alexander L, Mannion RO, Weingarten B, Fanelli RJ, Stiles GL. Development and impact of prescription opioid abuse deterrent formulation technologies. Drug Alcohol Depend. 2014;138:1-6. doi: 10.1016/j.drugalcdep.2014.02.006. DOI: https://doi.org/10.1016/j.drugalcdep.2014.02.006

Muppalaneni S, Mastropietro DJ, Omidian H. Crush resistance and insufflation potential of poly(ethylene oxide)-based abuse deterrent formulations. Expert Opin Drug Deliv. 2016;13(10):1375-1382. doi: 10.1080/17425247.2016.1211638. DOI: https://doi.org/10.1080/17425247.2016.1211638

Rahman Z, Yang Y, Korang-Yeboah M, Siddiqui A, Xu X, Ashraf M, et al. Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations. Int J Pharm. 2016;502(1-2):138-150. doi: 10.1016/j.ijpharm.2016.02.029. DOI: https://doi.org/10.1016/j.ijpharm.2016.02.029

Rahman Z, Zidan AS, Korang-Yeboah M, Yang Y, Siddiqui A, Shakleya D, et al. Effects of excipients and curing process on the abuse deterrent properties of directly compressed tablets. Int J Pharm. 2017;517(1-2):303-311. doi: 10.1016/j.ijpharm.2016.12.015. DOI: https://doi.org/10.1016/j.ijpharm.2016.12.015

Boyce HJ, Ibrahim A, Hoag SW. Physical barrier type abuse-deterrent formulations: monitoring sintering-induced microstructural changes in polyethylene oxide placebo tablets by near infrared spectroscopy (NIRS). Drug Dev Ind Pharm. 2018;44(11):1885-1894. doi: 10.1080/03639045.2018.1504965. DOI: https://doi.org/10.1080/03639045.2018.1504965

Yu D, Seelam RR, Zhang F, Byrn SR, Hoag SW. Evaluation of tableting performance of Poly (ethylene oxide) in abuse-deterrent formulations using compaction simulation studies. J Pharm Sci. 2021;110(7):2789-2799. doi: 10.1016/j.xphs.2021.03.008. DOI: https://doi.org/10.1016/j.xphs.2021.03.008

Ma L, Deng L, Chen J. Applications of poly(ethylene oxide) in controlled release tablet systems: a review. Drug Dev Ind Pharm. 2014;40(7):845-851. doi: 10.3109/03639045.2013.831438. DOI: https://doi.org/10.3109/03639045.2013.831438

Upadhye SB, Rajabi-Siahboomi AR. Properties and applications of polyethylene oxide and ethylcellulose for tamper resistance and controlled drug delivery. In: Repka MA, Langley N, DiNunzio J, (Eds.), Melt Extrusion: Materials, Technology and Drug Product Design, Springer New York; 2013. p. 145-158. doi: 10.1007/978-1-4614-8432-5_6. DOI: https://doi.org/10.1007/978-1-4614-8432-5_6

Rowe RC, Sheskey P, Quinn M. Handbook of pharmaceutical excipients, (6th Ed.), Pharmaceutical Press; 2009.

Crowley MM, Zhang F, Koleng JJ, McGinity JW. Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion. Biomaterials. 2002;23(21):4241-4248. doi: 10.1016/S0142-9612(02)00187-4. DOI: https://doi.org/10.1016/S0142-9612(02)00187-4

Boyce H, Smith D, Byrn S, Saluja B, Qu W, Gurvich VJ, et al. In vitro assessment of nasal insufflation of comminuted drug products designed as abuse deterrent using the vertical diffusion cell. AAPS PharmSciTech. 2018;19(4):1744-1757. doi: 10.1208/s12249-017-0947-2. DOI: https://doi.org/10.1208/s12249-017-0947-2

Boyce HJ, Dave VS, Scoggins M, Gurvich VJ, Smith DT, Byrn SR, et al. Physical barrier type abuse-deterrent formulations: mechanistic understanding of sintering-induced microstructural changes in polyethylene oxide placebo tablets. AAPS PharmSciTech. 2020;21:1-17. doi: 10.1208/s12249-019-1594-6. DOI: https://doi.org/10.1208/s12249-019-1594-6

Meruva S, Donovan MD. Effects of drug-polymer interactions on tablet properties during the development of abuse-deterrent dosage forms. AAPS PharmSciTech. 2019;20:1-12. doi: 10.1208/s12249-018-1221-y. DOI: https://doi.org/10.1208/s12249-018-1221-y

Carinci AJ. Abuse-deterrent opioid analgesics: a guide for clinicians. Pain Manag. 2020;10(1):55-62. doi: 10.2217/pmt-2019-0052. DOI: https://doi.org/10.2217/pmt-2019-0052

OxyContin® label. (Accessed on June 11, 2024). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022272s034lbl.pdf

RoxyBond® label. (Accessed 11 June 2024). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209777lbl.pdf

Troxyca® ER label. (Accessed 11 June 2024). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207621s004lbl.pdf

Meske D, Kopecky EA, Passik S, Shram MJ. Evaluation of the oral human abuse potential of oxycodone DETERx® formulation (Xtampza® ER). J Opioid Manag. 2018;14(5):359-372. doi: 10.5055/jom.2018.0468. DOI: https://doi.org/10.5055/jom.2018.0468

Kopecky EA, Fleming AB, Levy‐Cooperman N, O'Connor M, M. Sellers E. Oral human abuse potential of oxycodone DETERx®(Xtampza® ER). J Clin Pharmacol. 2017;57(4):500-512. doi: 10.1002/jcph.833. DOI: https://doi.org/10.1002/jcph.833

Harris SC, Cipriano A, Colucci SV, Kapil RP, Geoffroy P, Hopyan T, et al. Oral abuse potential, pharmacokinetics, and safety of once-daily, single-entity, extended-release hydrocodone (HYD) in recreational opioid users. Pain Med. 2017;18(7):1278-1291. doi: 10.1093/pm/pnw208. DOI: https://doi.org/10.1093/pm/pnw208

Arymo™ ER label. (Accessed on June 11, 2024). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208603s000lbl.pdf

Kinzler ER, Pantaleon C, Iverson MS, Aigner S. Syringeability of morphine ARER, a novel, abuse-deterrent, extended-release morphine formulation. Am J Drug Alcohol Abuse. 2019;45(4):377-384. doi: 10.1080/00952990.2019.1599383. DOI: https://doi.org/10.1080/00952990.2019.1599383

Webster LR, Pantaleon C, Shah MS, DiFalco R, Iverson M, Smith MD, et al. A randomized, double-blind, double-dummy, placebo-controlled, intranasal drug liking study on a novel abuse-deterrent formulation of morphine—morphine ARER. Pain Med. 2017;18(7):1303-1313. doi: 10.1093/pm/pnw213. DOI: https://doi.org/10.1093/pm/pnw213