Application of hot-melt extrusion technology in immediate-release abuse-deterrent formulations

Klaus Wening, PhD; Sebastian Schwier, PhD; Hans-J. Stahlberg, MD; Eric Galia, PhD

doi:10.5055/jom.2017.0422

Authors

Klaus Wening, PhD
Sebastian Schwier, PhD
Hans-J. Stahlberg, MD
Eric Galia, PhD

DOI:

https://doi.org/10.5055/jom.2017.0422

Keywords:

abuse-deterrent formulation, immediate-release, hot-melt extrusion

Abstract

Objective: Hot-melt extrusion (HME) technology has been used for manufacturing extended-release abuse-deterrent formulations (ADFs) of opioid-type analgesics with improved tamper-resistant properties. Our objective was to describe application of this technology to immediate-release (IR) ADFs.

Design: For development of a sample IR ADF (hydrocodone 10 mg/acetaminophen 325 mg) based on HME, feasibility studies were performed using different excipients. The formulation selected for further development was evaluated via in vitro test battery. Moreover, in vivo performance of IR ADF technologies was investigated in an open-label, randomized, cross-over, phase 1, relative oral bioavailability study with another opioid (model compound).

Setting: Single-center bioavailability trial.

Participants: Twenty-four healthy white male subjects.

Interventions: ADF IR formulation of an opioid and marketed IR formulation.

Main Outcome Measure(s): For feasibility and in vitro studies, dissolution profiles, syringeability, particle size distribution after physical manipulation, and extractability were evaluated. For the phase 1 study, pharmacokinetic parameters were evaluated and compared for ADF IR and a marketed IR formulation.

Results: After manipulation, the majority of particles from the ADF IR formulation were >500 μm and, thus, not considered suitable for intranasal abuse, while the majority of particles for the reference marketed IR formulation were <500 μm. The ADF IR formulation was resistant to syringing and preparation for potential intravenous injection. In healthy subjects, pharmacokinetics of an ADF and marketed IR formulation of an opioid were nearly identical.

Conclusions: Application of HME to IR formulations led to development of products with improved mechanical resistance to manipulation for intranasal or intravenous preparation, but similar bioavailability.

Author Biographies

Klaus Wening, PhD

Director, Grünenthal GmbH, Aachen, Germany

Sebastian Schwier, PhD

Project Director, Grünenthal GmbH, Aachen, Germany

Hans-J. Stahlberg, MD

Director, Grünenthal GmbH, Aachen, Germany

Eric Galia, PhD

Project Director, Grünenthal GmbH, Aachen, Germany

References

Substance Abuse and Mental Health Services Administration: Behavioral Health Trends in the United States: Results from the 2014 National Survey on Drug Use and Health. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2015.

United Nations Office on Drugs and Crime: World Drug Report 2016. (United Nations publication, Sales No. E.16.XI.7).

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; 65 (50-51): 1445-1452.

Katz N, Dart RC, Bailey E, et al.: Tampering with prescription opioids: nature and extent of the problem, health consequences, and solutions. Am J Drug Alcohol Abuse. 2011; 37 (4): 205-217.

Silva K, Schrager SM, Kecojevic A, et al.: Factors associated with history of non-fatal overdose among young nonmedical users of prescription drugs. Drug Alcohol Depend. 2013; 128: 104-110.

Butler SF, Black RA, Cassidy TA, et al.: Abuse risks and routes of administration of different prescription opioid compounds and formulations. Harm Reduct J. 2011; 8: 29.

Maincent J, Zhang F: Recent advances in abuse-deterrent technologies for the delivery of opioids. Int J Pharm. 2016; 510 (1): 57-72.

Vosburg SK, Jones JD, Manubay JM, et al.: Assessment of a formulation designed to be crush-resistant in prescription opioid abusers. Drug Alcohol Depend. 2012; 126 (1-2): 206-215.

Omidian A, Mastropietro DJ, Omidian H: Routes of opioid abuse and its novel deterrent formulations. J Develop Drugs. 2015; 4 (5).

Severtson SG, Ellis MS, Kurtz SP, et al.: Sustained reduction of diversion and abuse after introduction of an abuse deterrent formulation of extended release oxycodone. Drug Alcohol Depend. 2016; 168: 219-229.

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.

Iwanicki JL, Severtson SG, McDaniel H, et al: Abuse and diversion of immediate release opioid analgesics as compared to extended release formulations in the United States. PLoS One. 2016; 11 (12): e0167499.

Galia E, Williams Y, Van HB, et al.: Evaluation of the tamper-resistant properties of tapentadol extended-release tablets: Results of in vitro laboratory analyses. J Opioid Manag. 2014; 10 (3): 149-158.

Bartholomaeus JH, Arkenau-Maric E, Galia E: Opioid extended-release tablets with improved tamper-resistant properties. Expert Opin Drug Deliv. 2012; 9 (8): 879-891.

Bartholomäus J, Schwier S, Brett M, et al.: New abuse-deterrent formulation (ADF) technology for immediate-release opioids. Drug Develop Deliv. 2013; 13 (8): 76-81.

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER): General principles for evaluating the abuse deterrence of generic solid oral opioid drug products guidance for industry: draft guidance. US FDA. 2016.

Zscherpe J: Nasal powder formulations for systemic drug administration. Thesis 2008, Christian-Albrechts-University, Kiel (Germany).

Boomer R: Drug delivery: Nasal route. Encyclopedia of Pharmaceutical Technology, Third Edition. New York, NY: Informa Healthcare USA, Inc; 2007.

Suzuki Y, Ikura H, Yamashita G, et al.: Powdery pharmaceutical composition and powdery preparation for application to the nasal mucosa, and method for administration thereof. US 4,294,829. Oct 13, 1981.

Schwier S, Wening K, Stahlberg H: Comparison of invitro test characterization of immediate and extended release products with abuse deterrent features. Poster presented at PAINWeek, Las Vegas, Nevada, September 8-12, 2015.

Fransen N, Bjork E, Nystrom C: Development and characterization of interactive mixtures with a fine-particulate mucoadhesive carrier for nasal drug delivery. Eur J Pharm Biopharm. 2007; 67 (2): 370-376.

De Ascentiis A, Bettini R, Caponetti G, et al.: Delivery of nasal powders of beta-cyclodextrin by insufflation. Pharm Res. 1996; 13 (5): 734-738.

European Medicines Agency: Committee for Medicinal Products for Human Use (CHMP). Guideline on the investigation of bioequivalence. London, United Kingdom: European Medicines Agency; 2010.