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Current Drug Delivery


ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Review Article

Application of Hot Melt Extrusion Technology in the Development of Abuse-Deterrent Formulations: An Overview

Author(s): Arun Butreddy, Dinesh Nyavanandi, Sagar Narala, Fischer Austin and Suresh Bandari*

Volume 18, Issue 1, 2021

Published on: 17 August, 2020

Page: [4 - 18] Pages: 15

DOI: 10.2174/1567201817999200817151601

Price: $65


The misuse, abuse, and illicit use of prescription opioid analgesics is a global public health concern. However, there are many viable therapeutic options for the treatment of patients with chronic pain. Both intact and manipulated opioid drug products are abused by various routes such as oral, nasal, and injection, which may lead to overdose, drug addiction, and even death. To combat the abuse of these medications, regulatory agencies and pharmaceutical companies are switching their interest towards developing Abuse Deterrent Formulations (ADFs), with the intent to deter the abuse of opioid products to a maximum extent. There are several manufacturing strategies implemented in an attempt to develop ADFs. An example includes matrix tablets of high molecular weight polymers such as polyethylene oxide. The scalable and continuous manufacturing techniques, such as Hot-Melt Extrusion (HME), is increasingly accepted by pharmaceutical companies to advance the development and manufacturing of ADFs. The application of the HME technique in the development of ADFs may overcome the challenges of opioid analgesic formulation development and provide improved protection against misuse and abuse, while also ensuring access to safe and effective use in patients with chronic pain. This review deals with a brief overview of strategies, with emphasis on HME to deter opioid abuse, in vitro characterization methods, commonly used excipients in the development of ADFs, and regulatory standards to meet the requirements of ADFs.

Keywords: Hot melt extrusion, abuse, opioids, manipulation, abuse deterrent formulations, polymer.

Graphical Abstract
Kaye, A.D.; Jones, M.R.; Kaye, A.M.; Ripoll, J.G.; Jones, D.E.; Galan, V.; Beakley, B.D.; Calixto, F.; Bolden, J.L.; Urman, R.D.; Manchikanti, L. Prescription opioid abuse in chronic pain: an updated review of opioid abuse predictors and strategies to curb opioid abuse (part 2). Pain Physician, 2017, 20(2S), S111-S133.
[PMID: 28226334]
Strang, J.; Bearn, J.; Farrell, M.; Finch, E.; Gossop, M.; Griffiths, P.; Marsden, J.; Wolff, K. Route of drug use and its implications for drug effect, risk of dependence and health consequences. Drug Alcohol Rev., 1998, 17(2), 197-211. []. [PMID: 16203485].
Food and Drug Administration Abuse-deterrent opioids-evaluation and labeling.Guidance for Industry. 2020. regulatory-information/search-fda-guidance-documents/abuse-deterrent-opioids-evaluation-and-labeling
Walley, A.Y.; Xuan, Z.; Hackman, H.H.; Quinn, E.; Doe-Simkins, M.; Sorensen-Alawad, A.; Ruiz, S.; Ozonoff, A. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ, 2013, 346, f174. []. [PMID: 23372174].
Hale, M.E.; 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. []. [PMID: 27050830].
Jones, C.M. Reprint of trends and key correlates of prescription opioid injection misuse in the United States. Addict. Behav., 2018, 86, 24-31. []. [PMID: 30037685].
Webster, L.R.; Markman, J.; Cone, E.J.; Niebler, G. Current and future development of extended-release, abuse-deterrent opioid formulations in the United States. Postgrad. Med., 2017, 129(1), 102-110. []. [PMID: 27915497].
Crudele, N.; Giordano, J.; Mayock, S.P.; Saim, S.; Fleming, A.B. In Vitro drug release after crushing: evaluation of Xtampza® ER and other ER opioid formulations. Clin. Drug Investig., 2018, 38(8), 795-797. []. [PMID: 29949103].
Adler, J.A.; Mallick-Searle, T. An overview of abuse-deterrent opioids and recommendations for practical patient care. J. Multidiscip. Healthc., 2018, 11, 323-332. []. [PMID: 30026658].
US Food and Drug Administration. Drugs@FDA: FDA approved drug products, .
Mastropietro, D.J.; Omidian, H. Abuse-deterrent formulations: part 2: commercial products and proprietary technologies. Expert Opin. Pharmacother., 2015, 16(3), 305-323. []. [PMID: 25421961].
Rahman, Z.; Dharani, S.; Charoo, N.A.; Nutan, M.T.; Khan, M.A. Abuse deterrent formulations for reducing misuse and abuse of prescription opioids. Drug Abuse: Addict. Recover., 2016, 374, 1253-1263.
Food and Drug Administaration. Drug specific information on abuse deterrent opioid analgesics, 2019.
Cohen, J.P.; 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. []. [PMID: 29398162].
Mastropietro, D.J.; Omidian, H. Abuse-deterrent formulations: part 1 - development of a formulation-based classification system. Expert Opin. Drug Metab. Toxicol., 2015, 11(2), 193-204. []. [PMID: 25374404].
Stanos, S.P.; Bruckenthal, P.; Barkin, R.L. 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. []. [PMID: 22766088].
Davis, M.; Goforth, H.W.; Gamier, P. Oxycodone combined with opioid receptor antagonists: efficacy and safety. Expert Opin. Drug Saf., 2013, 12(3), 389-402. []. [PMID: 23534906].
Mastropietro, D.J.; Omidian, H. Current approaches in tamper-resistant and abuse-deterrent formulations. Drug Dev. Ind. Pharm., 2013, 39(5), 611-624. []. [PMID: 22537282].
Kumar, V.; Dixon, D.; Tewari, D.; Wadgaonkar, D.B. Methods and compositions for deterring abuse of opioid containing dosage forms., 2007.U.S. Patent 7,201,920 B2.
Maincent, J.; Zhang, F. Recent advances in abuse-deterrent technologies for the delivery of opioids. Int. J. Pharm., 2016, 510(1), 57-72. []. [PMID: 27291971].
Simon, K.; Worthy, S.L.; Barnes, M.C.; Tarbell, B. Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety. Ther. Adv. Drug Saf., 2015, 6(2), 67-79. []. [PMID: 25922655].
Pergolizzi, J.V., Jr; Raffa, R.B.; Taylor, R., Jr; Vacalis, S. Abuse-deterrent opioids: an update on current approaches and considerations. Curr. Med. Res. Opin., 2018, 34(4), 711-723. []. [PMID: 29262730].
Altomare, C.; Kinzler, E.R.; Buchhalter, A.R.; Cone, E.J.; 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. []. [PMID: 29308590].
Cone, E.J.; Sokolowska, M.; Lindhardt, K. Striving for consensus on approaches to category 1 testing of abuse‐deterrent formulations of opioids: discussions from the first category 1 focus group meeting. Pain Pract., 2016, 16(7), 809-813. []. [PMID: 27600925].
Food and Drug Administration; General principles for evaluating the abuse deterrence of generic solid oral opioid drug products., 2017.Available from:.
Kopecky, E.A.; Fleming, A.B.; Noonan, P.K.; Varanasi, R.K.; Grima, M.; Saim, S.; Mayock, S.P. Impact of physical manipulation on in vitro and in vivo release profiles of oxycodone DETERx®: an extended-release, abuse-deterrent formulation. J. Opioid. Manag., 2014, 10(4), 233-246. []. [PMID: 25162603].
Harris, S.C.; Cipriano, A.; Colucci, S.V.; Kapil, R.P.; Geoffroy, P.; Hopyan, T.; Levy-Cooperman, N. Intranasal abuse potential, pharmacokinetics, and safety of once-daily, single-entity, extended-release Hydrocodone (HYD) in recreational opioid users. Pain Med., 2016, 17(5), 820-831.
[PMID: 26814240]
Litman, R.S.; Pagán, O.H.; Cicero, T.J. Abuse-deterrent opioid formulations. Anesthesiology, 2018, 128(5), 1015-1026. []. [PMID: 29252508].
Meruva, S.; Donovan, M.D. Effects of drug-polymer interactions on tablet properties during the development of abuse-deterrent dosage forms. AAPS PharmSciTech, 2019, 20(3), 93. []. [PMID: 30690657].
Dharani, S.; Barakh Ali, S.F.; Afrooz, H.; Mohamed, E.M.; Cook, P.; Khan, M.A.; Rahman, Z. Development of methamphetamine abuse-deterrent formulations using sucrose acetate isobutyrate. J. Pharm. Sci., 2020, 109(3), 1338-1346. []. [PMID: 31862204].
Sarabu, S.; Bandari, S.; Kallakunta, V.R.; Tiwari, R.; Patil, H.; Repka, M.A. An update on the contribution of hot-melt extrusion technology to novel drug delivery in the twenty-first century: part II. Expert Opin. Drug Deliv., 2019, 16(6), 567-582. []. [PMID: 31046479].
Mendonsa, N.; Almutairy, B.; Kallakunta, V.R.; Sarabu, S.; Thipsay, P.; Bandari, S.; Repka, M.A. Manufacturing strategies to develop amorphous solid dispersions: an overview. J. Drug Deliv. Sci. Technol., 2019, 55101459 [].
Repka, M.A.; Bandari, S.; Kallakunta, V.R.; Vo, A.Q.; McFall, H.; Pimparade, M.B.; Bhagurkar, A.M. Melt extrusion with poorly soluble drugs - an integrated review. Int. J. Pharm., 2018, 535(1-2), 68-85. []. [PMID: 29102700].
Breitenbach, J. Melt extrusion: from process to drug delivery technology. Eur. J. Pharm. Biopharm., 2002, 54(2), 107-117. []. [PMID: 12191680].
Chokshi, R.; Zia, H. Hot-melt extrusion technique: a review. Iran. J. Pharm. Res., 2004, 3, 3-16.
Bandari, S.; Nyavanandi, D.; Kallakunta, V.R.; Janga, K.Y.; Sarabu, S.; Butreddy, A.; Repka, M.A. Continuous twin screw granulation - An advanced alternative granulation technology for use in the pharmaceutical industry. Int. J. Pharm., 2020, 580119215 []. [PMID: 32194206].
Kallakunta, V.R.; Patil, H.; Tiwari, R.; Ye, X.; Upadhye, S.; Vladyka, R.S.; Sarabu, S.; Kim, D.W.; Bandari, S.; Repka, M.A. Exploratory studies in heat-assisted continuous twin-screw dry granulation: a novel alternative technique to conventional dry granulation. Int. J. Pharm., 2019, 555, 380-393. []. [PMID: 30458256].
Crowley, M.M.; Zhang, F.; Repka, M.A.; Thumma, S.; Upadhye, S.B.; Battu, S.K.; McGinity, J.W.; Martin, C. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev. Ind. Pharm., 2007, 33(9), 909-926. []. [PMID: 17891577].
Kallakunta, V.R.; Tiwari, R.; Sarabu, S.; Bandari, S.; Repka, M.A. Effect of formulation and process variables on lipid based sustained release tablets via continuous twin screw granulation: a comparative study. Eur. J. Pharm. Sci., 2018, 121, 126-138. []. [PMID: 29772273].
Young, C.R.; Koleng, J.J.; McGinity, J.W. Production of spherical pellets by a hot-melt extrusion and spheronization process. Int. J. Pharm., 2002, 242(1-2), 87-92. []. [PMID: 12176229].
Kallakunta, V.R.; Sarabu, S.; Bandari, S.; Batra, A.; Bi, V.; Durig, T.; Repka, M.A. Stable amorphous solid dispersions of fenofibrate using hot melt extrusion technology: effect of formulation and process parameters for a low glass transition temperature drug. J. Drug Deliv. Sci. Technol., 2020, 58101395 [].
McGinity, J.W.; Zhang, F.; Koleng, J.; Repka, M.A. Hot-melt extrusion as a pharmaceutical process. Am. Pharmaceut. Rev., 2001, 4, 25-37.
Sarabu, S.; Kallakunta, V.R.; Bandari, S.; Batra, A.; Bi, V.; Durig, T.; Zhang, F.; Repka, M.A. Hypromellose acetate succinate based amorphous solid dispersions via hot melt extrusion: effect of drug physicochemical properties. Carbohydr. Polym., 2020, 233115828 []. [PMID: 32059882].
Maddineni, S.; Battu, S.K.; Morott, J.; Soumyajit, M.; Repka, M.A. Formulation optimization of hot-melt extruded abuse deterrent pellet dosage form utilizing design of experiments. J. Pharm. Pharmacol., 2014, 66(2), 309-322. []. [PMID: 24433429].
Xu, X.; Siddiqui, A.; Srinivasan, C.; Mohammad, A.; Rahman, Z.; Korang-Yeboah, M.; Feng, X.; Khan, M.; Ashraf, M. Evaluation of abuse-deterrent characteristics of tablets prepared via hot-melt extrusion. AAPS PharmSciTech, 2019, 20(6), 230. []. [PMID: 31227939].
Nukala, P.K.; Palekar, S.; Patki, M.; Fu, Y.; Patel, K. Multi-dose oral abuse deterrent formulation of loperamide using hot melt extrusion. Int. J. Pharm., 2019, 569118629 []. [PMID: 31425818].
Jedinger, N.; Schrank, S.; Fischer, J.M.; Breinhälter, K.; Khinast, J.; Roblegg, E. Development of an abuse-and alcohol-resistant formulation based on hot-melt extrusion and film coating. AAPS PharmSciTech, 2016, 17(1), 68-77. []. [PMID: 26206403].
Jedinger, N.; Schrank, S.; Mohr, S.; Feichtinger, A.; Khinast, J.; Roblegg, E. Alcohol dose dumping: the influence of ethanol on hot-melt extruded pellets comprising solid lipids. Eur. J. Pharm. Biopharm., 2015, 92, 83-95. []. [PMID: 25733499].
Baronsky-Probst, J.; Möltgen, C.V.; Kessler, W.; Kessler, R.W. Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production. Eur. J. Pharm. Sci., 2016, 87, 14-21. []. [PMID: 26386253].
Wening, K.; Schwier, S.; Stahlberg, H.J.; Galia, E.; Sokolowska, M. Application of hot-melt extrusion technology in immediate-release abuse-deterrent formulations. J. Opioid. Manag., 2017, 13(6), 473-484. []. [PMID: 29308593].
Rowe, R.C.; Sheskey, P.J.; Quinn, M.E. Handbook of pharmaceutical excipients, 6th ed; Pharmaceutical Press: London, 2009.
Zhang, F.; McGinity, J.W. Properties of sustained-release tablets prepared by hot-melt extrusion. Pharm. Dev. Technol., 1999, 4(2), 241-250. []. [PMID: 10231885].
Muppalaneni, S.; Mastropietro, D.J.; Omidian, H. Crush resistance and insufflation potential of poly(ethylene oxide)-based abuse deterrent formulations. Expert Opin. Drug Deliv., 2016, 13(10), 1375-1382. []. [PMID: 27402156].
Arca, H.C.; Mosquera-Giraldo, L.I.; Bi, V.; Xu, D.; Taylor, L.S.; Edgar, K.J. Pharmaceutical applications of cellulose ethers and cellulose ether esters. Biomacromolecules, 2018, 19(7), 2351-2376. []. [PMID: 29869877].
Tiwari, S.B.; Rajabi-Siahboomi, A.R. Extended-release oral drug delivery technologies: monolithic matrix systems. Methods Mol. Biol., 2008, 437, 217-243. []. [PMID: 18369971].
Jedinger, N.; Khinast, J.; Roblegg, E. The design of controlled-release formulations resistant to alcohol-induced dose dumping--a review. Eur. J. Pharm. Biopharm., 2014, 87(2), 217-226. []. [PMID: 24613542].
Ma, D.; Djemai, A.; Gendron, C.M.; Xi, H.; Smith, M.; Kogan, J.; Li, L. Development of a HPMC-based controlled release formulation with Hot Melt Extrusion (HME). Drug Dev. Ind. Pharm., 2013, 39(7), 1070-1083. []. [PMID: 22803806].
Rahman, Z.; Zidan, A.S.; Korang-Yeboah, M.; Yang, Y.; Siddiqui, A.; Shakleya, D.; Khan, M.A.; Cruz, C.; Ashraf, M. Effects of excipients and curing process on the abuse deterrent properties of directly compressed tablets. Int. J. Pharm., 2017, 517(1-2), 303-311. []. [PMID: 27956191].
Gómez-Carracedo, A.; Alvarez-Lorenzo, C.; Gómez-Amoza, J.; Concheiro, A. Chemical structure and glass transition temperature of non-ionic cellulose ethers. J. Therm. Anal. Calorim., 2003, 73(2), 587-596. [].
Vaka, S.R.K.; Bommana, M.M.; Desai, D.; Djordjevic, J.; Phuapradit, W.; Shah, N. Excipients for amorphous solid dispersions. Amorphous Solid Dispersions; Shah, N.; Sandhu, H.; Choi, D.; Chokshi, H.; Malick, A., Eds.; Springer: New York, 2014, pp. 123-161. []
Eastman chemical company. Eastman BioSustane™ SAIB (Sucrose acetate isobutyrate) pharma grade for the development of abusedeterrent formulations of opioid drugs, Available from: . https://www.
Ashland specialty ingredients; KlucelTM hydroxypropylcellulose,.
Schrank, S.; Jedinger, N.; Wu, S.; Piller, M.; Roblegg, E. Pore blocking: an innovative formulation strategy for the design of alcohol resistant multi-particulate dosage forms. Int. J. Pharm., 2016, 509(1-2), 219-228. []. [PMID: 27282540].
Kelco, C.P. Xanthan gum., 2020.Available from: . https://www.cpkelco. com/products/xanthan-gum/
Malm, C.J.; Emerson, J.; Hiatt, G.D. Cellulose acetate phthalate as an enteric coating material. J. Am. Pharm. Assoc., 1951, 40(10), 520-525. []. [PMID: 14907449].
Shanbhag, A.; Barclay, B.; Koziara, J.; Shivanand, P. Application of cellulose acetate butyrate-based membrane for osmotic drug delivery. Cellulose, 2007, 14(1), 65-71. [].
Becker, K.; Salar-Behzadi, S.; Zimmer, A. Solvent-free melting techniques for the preparation of lipid-based solid oral formulations. Pharm. Res., 2015, 32(5), 1519-1545. []. [PMID: 25788447].
Jannin, V.; Rodier, J.D.; Musakhanian, J. Polyoxylglycerides and glycerides: effects of manufacturing parameters on API stability, excipient functionality and processing. Int. J. Pharm., 2014, 466(1-2), 109-121. []. [PMID: 24607211].
Ahmad, R.; Omidian, H. Development and in vitro evaluation of an abuse-deterrent formulation based on a crosslinked starch derivative. Int. J. Pharm., 2019, 569118602 []. [PMID: 31394182].
Ravenelle, F.; Rahmouni, M. Contramid®: high-amylose starch for controlled drug delivery. Polysaccharides for drug delivery and pharmaceutical applications. Marchessault, R.H.; Ravenelle, F.; Zhu. X.X; ACS Publications: Washington, 2006, Vol. 934, pp. 79-104. []
Shah, U.; Augsburger, L. Multiple sources of sodium starch glycolate, NF: evaluation of functional equivalence and development of standard performance tests. Pharm. Dev. Technol., 2002, 7(3), 345-359. []. [PMID: 12229266].
Alaei, S.; Babanejad, N.; Ahmad, R.; Omidian, H. Polymers and hydrogels to deter drug abuse., Engr. Drug Deliv. Syst., 2020, pp. 185-202.
Nukala, P.K.; Palekar, S.; Patki, M.; Patel, K. Abuse deterrent immediate release egg-shaped tablet (egglets) using 3D printing technology: quality by design to optimize drug release and extraction. AAPS PharmSciTech, 2019, 20(2), 80. []. [PMID: 30645704].
Evonik industries EUDRAGIT® EPO copolymer, Available from:.
D’Souza, S.; Mayock, S.; Salt, A. A review of in vivo and in vitro aspects of alcohol-induced dose dumping. AAPS Open, 2017, 3(5), 1-20. [].
BASF chemicals company. Kollidon® SR. Available from: . https://
Rosiaux, Y.; Velghe, C.; Muschert, S.; Chokshi, R.; Leclercq, B.; Siepmann, F.; Siepmann, J. Ethanol-resistant ethylcellulose/guar gum coatings--importance of formulation parameters. Eur. J. Pharm. Biopharm., 2013, 85(3 Pt B), 1250-1258. []. [PMID: 23891769].
Wasilewska, K.; Winnicka, K. Ethylcellulose–a pharmaceutical excipient with multidirectional application in drug dosage forms development. Materials (Basel), 2019, 12(20), 3386. []. [PMID: 31627271].
Food and Drug Administration; FDA press announcements on benefit-risk framework for evaluating opioid analgesics., 2019. Available from: .
Food and Drug Administration; FDA news release on requests removal of Opana ER for risks related to abuse., 2017.Available from:.
Loeser, K.C.; Rodriguez, R. Regulatory and evidence-based considerations for abuse-deterrent opioids. Am. J. Health Syst. Pharm., 2019, 76(2), 114-118. []. [PMID: 30689701].

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