AAPS PharmSciTech

, Volume 19, Issue 4, pp 1744–1757 | Cite as

In Vitro Assessment of Nasal Insufflation of Comminuted Drug Products Designed as Abuse Deterrent Using the Vertical Diffusion Cell

  • Heather Boyce
  • Dan Smith
  • Steve Byrn
  • Bhawana Saluja
  • Wen Qu
  • Vadim J. Gurvich
  • Stephen W. Hoag
Research Article


In vitro evaluation of abuse deterrent formulations (ADFs) is a challenge since real abuse situations are variable and ADF technology is evolving. Specifically, an assessment of an ADF to deter nasal insufflation would be valuable. In this study, a vertical diffusion cell (VDC) was used to evaluate polyethylene oxide (PEO)-based tablets manipulated by three different forces. The commercially available products Oxycontin®, an ADF, Opana®, and metoprolol tartrate tablet formulations made in our laboratory were studied. Particle size distribution and percent recovery of manipulated tablets were measured. Grinding produced the lowest recovery and the smallest particle size distribution. Drug release was examined using a VDC by placing the dry comminuted particles on an enclosed wetted cellulose membrane. Dispensing dry particles on a VDC is atypical but includes some key features associated with an abuse situation where once the particles are snorted, the moisture in the nasal mucosa activates hydration and swelling of the polymers in the formulation, retarding drug release. Drug release from OxyContin®, Opana®, and metoprolol tablets were analyzed for the cutting, grinding, and milling modes of abuse. The analysis showed that in most cases, the mode of abuse produced different particle sizes with different release rates. Statistically different release rates were observed for metoprolol tablets made with different molecular weight PEO and with different porosities. These results indicate that within detection limits, the VDC can be used to quantitate release differences due to various modes of abuse used in this study.


abuse deterrent formulations (ADFs) oxycontin® Opana® ER vertical diffusion cell (VDC) polyethylene oxide (PEO) 



The authors would like to acknowledge Hanson Research Corporation for the generous use of equipment to conduct the diffusion studies; Dow Chemical for their donation of various POLYOX grades; Noramco for their donation of oxycodone HCl and oxymorphone HCl reference material. The authors would also like to acknowledge PhRMA foundation, the National Institute for Pharmaceutical Technology and Education (NIPTE), and the US Food and Drug Administration (FDA) for providing funds for this research. This study was funded by the FDA GDUFA contract to NIPTE (# HHSF223201301189P). This work was submitted in partial fulfillment of Ph.D requirement for Heather Boyce.

Compliance with Ethical Standards


Views expressed in this publication do not necessarily reflect the official policies of the FDA, nor does any mention of trade names, commercial practices, or organization imply endorsement by the FDA.

This paper was written in partial fulfillment of a Ph.D. thesis.


  1. 1.
    Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-involved overdose deaths—United States, 2010–2015. MMWR Morb Mortal Wkly Rep 2016: Center for Disease Control; 2016. p. 1445–52.Google Scholar
  2. 2.
    Katz N. Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep. 2008;10(1):11–8. Scholar
  3. 3.
    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. Scholar
  4. 4.
    Moorman-Li R, Motycka CA, Inge LD, Congdon JM, Hobson S, Pokropski B. A review of abuse-deterrent opioids for chronic nonmalignant pain. Pharmacy and Therapeutics. 2012;37(7):412–8.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Romach MK, Schoedel KA, Sellers EM. Update on tamper-resistant drug formulations. Drug Alcohol Depend. 2013;130(1–3):13–23. Scholar
  6. 6.
    Medical CfDEaRC. Abuse-deterrent opioids—evaluation and labeling. In: Services USDoHaH, Administration FaD, editors. 2015.Google Scholar
  7. 7.
    Research CfDEa. General principles for evaluating the abuse deterrence of generic solid oral opioid drug products. In: Services USDoHaH, Administration FaD, editors. 2016.Google Scholar
  8. 8.
    Xu X, Gupta A, Al-Ghabeish M, Calderon SN, Khan MA. Risk based in vitro performance assessment of extended release abuse deterrent formulations. Int J Pharm. 2016;500(1-2):255–67. Scholar
  9. 9.
    Maincent J, Zhang F. Recent advances in abuse-deterrent technologies for the delivery of opioids. Int J Pharm. 2016;510(1):57–72. Scholar
  10. 10.
    Setnik B, Sommerville K, Goli V, Han L, Webster L. Assessment of pharmacodynamic effects following oral administration of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules compared with crushed morphine sulfate controlled-release tablets and placebo in nondependent recreational opioid users. Pain Med. 2013;14(8):1173–86. Scholar
  11. 11.
    Badalamenti VC, Buckley JW, Smith ET. Safety of EMBEda (morphine sulfate and naltrexone hydrochloride) extended-release capsules: review of postmarketing adverse events during the first year. J Opioid Manag. 2012;8(2):115–25. Scholar
  12. 12.
    Harris SC, Cipriano A, Kapil RP, Levy-Cooperman N, Colucci SV, Geoffroy P, et al. Oral Abuse potential, pharmacokinetics, and safety of once-daily, single-entity, extended-release hydrocodone (HYD) in recreational opioid users. Pain medicine (Malden, Mass). 2016.Google Scholar
  13. 13.
    Dhillon S. Hydrocodone Bitartrate ER (Hysingla® ER): a review in chronic pain. Clin Drug Investig. 2016;36(11):969–80. Scholar
  14. 14.
    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 medicine (Malden, Mass). 2016.Google Scholar
  15. 15.
    Gudin J. Oxycodone DETERx(R): a novel abuse-deterrent, extended-release analgesic option for the treatment of patients with chronic pain. Pain and therapy. 2016;5(2):171–86. Scholar
  16. 16.
    Kopecky EA, Fleming AB, Levy-Cooperman N, O'Connor M, EM Sellers. Oral human abuse potential of oxycodone DETERx(R) (Xtampza(R) ER). J Clin Pharmacol 2016.Google Scholar
  17. 17.
    Backonja M, Webster LR, Setnik B, Bass A, Sommerville KW, Matschke K, et al. Intravenous abuse potential study of oxycodone alone or in combination with naltrexone in nondependent recreational opioid users. Am J Drug Alcohol Abuse. 2016;42(5):539–49. Scholar
  18. 18.
    Harris AS, Svensson E, Wagner ZG, Lethagen S, Nilsson IM. Effect of viscosity on particle size, deposition, and clearance of nasal delivery systems containing desmopressin. J Pharm Sci. 1988;77(5):405–8. Scholar
  19. 19.
    Perrino P, Colucci S, Apseloff G, Harris S. Pharmacokinetics, tolerability, and safety of intranasal administration of reformulated OxyContin tablets compared with original OxyContin tablets in healthy adults. Clin Drug Investig. 2013;33(6):441–9. Scholar
  20. 20.
    Bartholomaus J, Kugelmann H, Arkenau-Marić E, inventors; Google Patents, assignee. Abuse-proofed dosage form. United States patent 8309060 B2. 2012.Google Scholar
  21. 21.
    McGinity JW, Zhang F. InventorsHot-melt extrudable pharmaceutical formulation. United States patent 6488963 B1. 2002.Google Scholar
  22. 22.
    Cone EJ, Giordano J, Weingarten B. An iterative model for in vitro laboratory assessment of tamper deterrent formulations. Drug Alcohol Depend. 2013;131(1-2):100–5. Scholar
  23. 23.
    Katz NP, Buse DC, Budman SH, Wing Venuti S, Fernandez KC, Benoit C, et al. Development and preliminary experience with an ease of extractability rating system for prescription opioids. Drug Dev Ind Pharm. 2006;32(6):727–46. Scholar
  24. 24.
    Butler SF, Benoit C, Budman SH, Fernandez KC, McCormick C, Venuti SW, et al. Development and validation of an Opioid Attractiveness Scale: a novel measure of the attractiveness of opioid products to potential abusers. Harm Reduction J. 2006;3(1):5. Scholar
  25. 25.
    Cone EJ, Buchhalter AR, Wang DW, Henningfield J. Alerrt™ visual analog scale: assessing “work” requirements associated with tampering of abuse-deterrent opioid formulations. Drug Alcohol Depend. 2015;156:e46–e7. Scholar
  26. 26.
    Harris SC, Perrino PJ, Smith I, Shram MJ, Colucci SV, Bartlett C, et al. Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol. 2014;54(4):468–77. Scholar
  27. 27.
    Harris SC, Cipriano A, Colucci SV, Kapil RP, Geoffroy P, Hopyan T, et al. Intranasal abuse potential, pharmacokinetics, and safety of once-daily, single-entity, extended-release hydrocodone (HYD) in recreational opioid users. Pain medicine: the official journal of the American Academy of Pain Med. 2016;17(5):820–31. Scholar
  28. 28.
    Vosburg SK, Jones JD, Manubay JM, Ashworth JB, Shapiro DY, Comer SD. A comparison among tapentadol tamper-resistant formulations (TRF) and OxyContin® (non-TRF) in prescription opioid abusers. Addiction. 2013;108(6):1095–106. Scholar
  29. 29.
    Monteiro-Riviere NA, Popp JA. Ultrastructural characterization of the nasal respiratory epithelium in the rat. Am J Anat. 1984;169(1):31–43. Scholar
  30. 30.
    Merkus FW, Verhoef JC, Schipper NG, Marttin E. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Deliv Rev. 1998;29(1–2):13–38.PubMedGoogle Scholar
  31. 31.
    Charlton S, Jones NS, Davis SS, Illum L. Distribution and clearance of bioadhesive formulations from the olfactory region in man: effect of polymer type and nasal delivery device. Eur J Pharm Sci. 2007;30(3–4):295–302. Scholar
  32. 32.
    Proctor DF, Adams GK, Andersen I, Man SF. Nasal mucociliary clearance in man. CIBA Found Symp. 1978;54:219–34.Google Scholar
  33. 33.
    Chaturvedi M, Kumar M, Pathak K. A review on mucoadhesive polymer used in nasal drug delivery system. J Adv Pharm Technol Res. 2011;2(4):215–22. Scholar
  34. 34.
    Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv Transl Res. 2013;3(1):42–62. Scholar
  35. 35.
    Gaikwad V. Formulation and evaluation of in-situ gel of metoprolol tartrate for nasal delivery. J Pharm Res. 2010;3(4):788–93.Google Scholar
  36. 36.
    Kurti L, Gaspar R, Marki A, Kapolna E, Bocsik A, Veszelka S, et al. In vitro and in vivo characterization of meloxicam nanoparticles designed for nasal administration. Eur J Pharm Sci. 2013;50(1):86–92. Scholar
  37. 37.
    Pardeshi CV, Belgamwar VS, Tekade AR, Surana SJ. Novel surface modified polymer-lipid hybrid nanoparticles as intranasal carriers for ropinirole hydrochloride: in vitro, ex vivo and in vivo pharmacodynamic evaluation. J Mater Sci Mater Med. 2013;24(9):2101–15. Scholar
  38. 38.
    Scheuplein RJ, Ross LW. Mechanism of percutaneous absorption. V. Percutaneous absorption of solvent deposited solids. J Investig Dermatol. 1974;62(4):353–60. Scholar
  39. 39.
    Kim CJ. Drug release from compressed hydrophilic POLYOX-WSR tablets. J Pharm Sci. 1995;84(3):303–6. Scholar
  40. 40.
    Maggi L, Segale L, Torre ML, Ochoa ME, Conte U. Dissolution behaviour of hydrophilic matrix tablets containing two different polyethylene oxides (PEOs) for the controlled release of a water-soluble drug. Dimensionality study. Biomaterials. 2002;23(4):1113–9. Scholar
  41. 41.
    Savas H, Guven O. Investigation of active substance release from poly(ethylene oxide) hydrogels. Int J Pharm. 2001;224(1–2):151–8. Scholar
  42. 42.
    Hussain MA, Aungst BJ. Intranasal absorption of oxymorphone. J Pharm Sci. 1997;86(8):975–6. Scholar
  43. 43.
    Nasal Systematic Drug Delivery. Chien YW, Su KSE, Chang S-F, editors. New York, NY: Marcel Dekker Inc; 1989. 310 p.Google Scholar
  44. 44.
    Services USDoHaH, Administration FaD. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. In: (CDER) CfDEaR, editor. Guidance for Industry. 1 ed05/04/2015.Google Scholar
  45. 45.
    Thakker K. Theory and applications of vertical diffusion cells for characterization of topical and other dosage forms. Tergus pharma, LLC.Google Scholar
  46. 46.
    Peters PJ, Pontones P, Hoover KW, Patel MR, Galang RR, Shields J, et al. HIV infection linked to injection use of oxymorphone in Indiana, 2014-2015. N Engl J Med. 2016;375(3):229–39. Scholar
  47. 47.
    Byrn S, Smith D, Fang K, Hajec C, Boyce H, Saluja B, et al. Failure modes and dose dumping of opioid drug products including abuse-deterrent opioid drug products. J Pharm Sci. 2017;Manuscript ID 16–1226 Accepted.Google Scholar
  48. 48.
    Boyce H, Smith DT, Byrn S, Saluja B, Qu W, Gurvich V, et al. Investigation of abuse deterrent properties of sintered polyethylene oxide and hypromellose placebo tablets. Am Assoc Pharm Sci Ann Meet; Orlando, Fl 2015.Google Scholar
  49. 49.
    Parrott EL. Milling of pharmaceutical solids. J Pharm Sci. 1974;63(6):813–29. Scholar
  50. 50.
    Arias MJ, Gines JM, Moyano JR, Rabasco AM. Dissolution properties and in vivo behaviour of triamterene in solid dispersions with polyethylene glycols. Pharm Acta Helv. 1996;71(4):229–35. Scholar
  51. 51.
    Costa FO, Sousa JJ, Pais AA, Formosinho SJ. Comparison of dissolution profiles of ibuprofen pellets. J Controlled Release. 2003;89(2):199–212. Scholar
  52. 52.
    Peppas NA. Analysis of Fickian and non-Fickian drug release from polymers. Pharm Acta Helv. 1985;60(4):110–1.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Heather Boyce
    • 1
  • Dan Smith
    • 2
  • Steve Byrn
    • 2
    • 3
  • Bhawana Saluja
    • 4
  • Wen Qu
    • 4
  • Vadim J. Gurvich
    • 3
    • 5
  • Stephen W. Hoag
    • 1
    • 3
  1. 1.Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreUSA
  2. 2.Department of Industrial and Physical PharmacyPurdue UniversityIndianaUSA
  3. 3.Center of Excellence for Abuse Deterrent Opioid Technologies, NIPTEMinneapolisUSA
  4. 4.Center for Drug Evaluation and Research, U.S. Food and Drug AdministrationSilver SpringUSA
  5. 5.National Institute for Pharmaceutical Technology and Education (NIPTE)MinneapolisUSA

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