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`ABUSE DETERRENTABUSE DETERRENT
`
`T E C H N O L O G Y
`
`New Abuse Deterrent Formulation (ADF)
`Technology for Immediate-Release Opioids
`By: Johannes Bartholomäus(cid:0), PhD; Sebastian Schwier, PhD; Martin Brett, Hans-Jürgen Stahlberg, MD;
`Eric Galia, PhD; and Kai Strothmann, PhD
`
`INTRODUCTION
`
`F I G U R E 1
`
`Despite the recent introduction to the
`
`market of extended release (ER) opioid
`
`analgesics (re-)formulated with abuse
`
`deterrent (AD) properties, prescription
`
`opioid abuse in the US is an ongoing
`
`epidemic.1 In reaction to these abuse
`
`deterrent formulation (ADF) products,
`
`abusers “are shifting away from the new
`
`tamper-resistant formulations to non-
`
`tamper-resistant formulations of other
`
`opioids,” thus the need to turn more
`
`opioid analgesics into ADFs remains
`
`high.2 Meanwhile, the FDA has issued the
`
`“Draft Guidance for Industry Abuse-
`
`Deterrent Opioids – Evaluation and
`
`Labeling” to define a framework for
`
`development, characterization,
`
`premarketing, and post-marketing studies
`
`for assessment of AD features.3 In
`
`addition, the document suggests examples
`
`of labeling that may eventually be
`
`assigned to new AD formulations. The
`
`first ADFs to come to the market have
`
`concentrated on ER products as these
`
`contain significantly more active
`
`ingredient per tablet than immediate-
`
`release (IR) forms. These new ADFs
`
`predominantly apply crush-resistance
`
`technology for enhanced physicochemical
`
`properties. With reformulated
`
`OxyContin® CR (ORF in 2010),
`
`Nucynta® ER (2011), and reformulated
`
`INTAC® manufacturing concept for ER and IR products.
`
`F I G U R E 2
`
`In vitro profiles of INTAC® ER bid/oad and INTAC® IR formulations.
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`
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`F I G U R E 3
`
`In vitro release of a marketed model opioid from INTAC® IR tablet and conventional IR tablet.
`
`ER, which was still available in the non-crush
`
`investigate whether the crush-resistance
`
`resistant form at the time reformulated
`
`technology that has proven its merits for ER
`
`Oxycontin CR was launched) as well as to IR
`
`opioid products can be applied to IR forms.
`
`opioid products.8 Consequently, IR
`
`formulations should also become a greater
`
`focus in ADF concepts. A first concept using
`
`nasal irritants was introduced to the market in
`
`form of the oxycodone IR product Oxecta®,
`
`although no post-marketing surveillance data
`
`on this product have so far been published.
`
`The next logical step would therefore be to
`
`DESIGN OF INTAC® IR
`
`INTAC® is Grünenthal’s proprietary drug
`
`delivery platform of crush-resistant
`
`formulations already used in marketed opioid
`
`ER products.9,10 Unlike with ER formulations,
`
`crushing of IR tablets for oral abuse does not
`
`F I G U R E 4
`
`Attempt to prepare INTAC® IR tablet for intravenous abuse.
`
`Opana® ER (CRF in 2012), three products
`
`using such technology are currently available
`
`in the US market. Significant reduction in
`
`abuse after introduction of the reformulation
`
`has been demonstrated by post-marketing
`
`surveillance data for OxyContin CR and
`
`Opana ER mainly for non-oral routes of abuse
`
`such as nasal abuse (snorting, for both
`
`products) and intravenous injections
`
`(predominantly for OxyContin CR because
`
`Opana ER intravenous abuse rates were
`
`already low).4,5 For Nucynta ER on the other
`
`hand, such comparisons with earlier non-
`
`ADFs are not possible because this product
`
`was launched for the first time already as a
`
`crush-resistant formulation. In accordance
`
`with the aforementioned “Draft Guidance for
`
`Industry Abuse-Deterrent Opioids –
`
`Evaluation and Labeling”, the FDA very
`
`recently approved the first AD labeling, which
`
`was granted for reformulated OxyContin.6,7
`
`This was based on the results of laboratory
`
`manipulation and extraction studies, abuse
`
`liability studies comparing drug liking of
`
`manipulated reformulated OxyContin ORF
`
`with original OxyContin and oxycodone HCl
`
`powder, and post-marketing surveillance data.
`
`“The new labeling indicates that the product
`
`has physical and chemical properties that are
`
`expected to make abuse via injection difficult
`
`and to reduce abuse via the intranasal route
`
`(snorting).”6 The FDA determined further that
`
`the original formulation of OxyContin was
`
`withdrawn for reasons of safety or
`
`effectiveness and, thus, ANDAs relying on
`
`original OxyContin will not be accepted or
`
`approved. This case underpins the FDA’s
`
`positive position on ADFs and sets the stage
`
`for regulatory endorsement and labeling
`
`options of future ADFs for opioid products.
`
`After introduction of the first crush-
`
`resistant opioid ER products, abuse has been
`
`redirected to both unprotected ER
`
`formulations (initially also including Opana
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`F I G U R E 5
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`Particle sizes after tampering of tablets for preparation for nasal abuse.
`
`significantly alter their inherent fast-release
`
`requirements from IR through twice-daily up
`
`profile. Therefore the focus in extending the
`
`to once-daily ER applications (Figure 2).
`
`amongst others, a high molecular weight
`
`polyethylene oxide (PEO). The resulting
`
`crush-resistant pellets were subsequently
`
`mixed with easily compressible excipients.
`
`This blend was compressed to a tablet that
`
`releases the opioid in the same fashion as a
`
`conventional marketed IR tablet of the same
`
`opioid (Figure 3).
`
`The INTAC IR tablet was subjected to in
`
`vitro tamper-resistance testing by
`
`manipulations reflecting preparation for
`
`intravenous and nasal abuse. In order to test
`
`for impedance of intravenous abuse, INTAC
`
`multiparticulate IR tablets were prepared
`
`simulating the typical abuser procedure for
`
`intravenous administration trying to obtain a
`
`powder that can be extracted, preferably by
`
`water. Due to the gelling properties of the
`
`excipients used in the formulation, attempts to
`
`draw the resulting extract into a syringe
`
`(typically done with a cigarette filter by the
`
`experienced intravenous abuser) were
`
`IN VITRO TAMPER-RESISTANCE
`TESTING
`
`To verify the design concept for IR
`
`unsuccessful, and virtually no extract could be
`
`opioids, INTAC IR tablets were manufactured
`
`drawn up into the syringe (Figure 4).
`
`by HME of an opioid model compound
`
`together with a proprietary mix of ingredients,
`
`For testing of impeding nasal abuse,
`
`INTAC multiparticulate IR tablets were
`
`F I G U R E 6
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`79
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`Mean serum concentration-time profiles of a model opioid administered in form of INTAC® IR
`tablets and as a conventional IR tablet market product.
`
`INTAC formulation platform is to impede
`
`preparation for non-oral abuse of IR products
`
`without impacting the IR functionality.
`
`Consequently, a multiparticulate tamper-
`
`resistant INTAC tablet has been developed
`
`that is characterized by a distinct gelling
`
`quality that leads to low extraction rates and
`
`raises the hurdles against intravenous abuse.
`
`This feature is combined with pronounced
`
`resistance to crushing of the multiparticulate
`
`drug matrix, thereby inhibiting preparation for
`
`subsequent nasal abuse. The manufacturing
`
`concept for this approach is based on creating
`
`crush-resistant material by the versatile core
`
`technology of hot melt extrusion (HME). The
`
`same first step of HME is employed as for
`
`INTAC ER, but a different downstream
`
`process using a plurality of smaller dies and
`
`cutting by a pelletizer delivers AD IR pellets
`
`or granules (Figure 1) that can be further
`
`processed into IR tablets.
`
`With the addition of this IR concept, it is
`
`now possible to tailor release profiles from
`
`minutes up to about 1 day. Thus, INTAC
`
`becomes available as the solution for ADFs
`
`over the whole range of drug-release
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`KASHIV1057
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`

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`prepared simulating a typical abuser
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`procedure for nasal administration by
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`comminution. Even with a sophisticated
`
`manipulation technique, obtaining particle
`
`sizes < 500 microns for nasal abuse was
`
`substantially limited for the INTAC IR
`formulation (about 85% ≥ 500 microns). In
`
`contrast, the conventional IR tablet could
`
`easily be broken down far below 500 microns,
`
`about 80% < 500 microns (Figure 5). 500
`
`microns was set as a limit well above the
`
`typical particle sizes known to be suitable for
`
`nasal administration of compounds.
`
`These results from the laboratory tamper-
`
`resistance testing support the concept based
`
`on the chosen physicochemical approach
`
`showing that INTAC IR has the potential to
`
`impede abuse of IR opioids by non-oral
`
`administration routes.
`
`T A B L E 1
`
`Statistical evaluation of mean pharmacokinetic parameters of a model opioid administered in
`form of INTAC® IR tablets and as a conventional IR tablet market product.
`
`commonly used for assessing bioequivalence.
`
`demonstrated its versatility and broad
`
`SUMMARY
`
`applicability to both ER formulations, already
`
`available as marketed products, and to IR
`
`formulations that are coming more into focus
`
`for prescription opioid abuse. N
`
`CLINICAL DEVELOPMENT
`
`In order to cope with the increasing
`
`abuse of IR opioids after introduction of AD
`
`To verify that the change to an ADF
`
`formulations for ER opioid products, the
`
`formulation does not negatively impact the
`
`INTAC technology platform has been
`
`REFERENCES
`
`desired IR features of the product when
`
`patients take the product by the intended oral
`
`route, a bioavailability trial comparing the
`
`previously described INTAC IR model
`
`product to a marketed conventional IR
`
`formulation was performed. In an open,
`
`randomized, two-treatment, two-period, two-
`
`sequence cross-over design study with 24
`
`healthy volunteers (22 completed) the relative
`
`bioavailability of the two products was
`
`evaluated.11 The mean serum concentration
`
`curves of the model opioid from both
`
`formulations were almost superimposable
`
`extended to IR formulations with the intention
`
`1. CDC: Prescription Drug Overdose: An
`
`to deter their non-oral routes of abuse. In vitro
`
`American Epidemic.
`
`tampering tests have shown convincing results
`
`http://www.cdc.gov/about/
`
`with regard to impeding nasal and intravenous
`
`grandrounds/archives/2011/pdfs/PHGRRx1
`
`abuse. Although INTAC IR’s multiparticulate
`
`7Feb2011.pdf. (assessed July 3rd, 2013).
`
`drug matrix is difficult to pulverize and
`
`2. National Association of Attorneys General
`
`dissolve, the in vivo performance is
`
`letter (signed by 48 state & territorial
`
`nonetheless entirely comparable to the
`
`Attorney Generals) to the FDA, March
`
`marketed conventional IR product as the 90%
`
`2013.http://www.hpm.com/pdf/blog/20130
`
`confidence intervals for the ratios of the mean
`
`311.Final%20FDA%20
`
`PK parameters Cmax and AUC fulfilled the
`
`Letter.pdf. (assessed July 3rd, 2013).
`
`conditions commonly used for assessing
`
`3. FDA Draft Guidance for Industry Abuse-
`
`bioequivalence. The safety and tolerability
`
`Deterrent Opioids – Evaluation and
`
`over the whole investigation time (Figure 6).
`
`data of the INTAC IR formulation were
`
`Labeling http://www.fda.gov/downloads/
`
`The statistical evaluation of the
`
`pharmacokinetic parameters (Table 1) showed
`
`that the 90% confidence intervals (CI) for the
`
`equally in line with the marketed IR reference
`
`Drugs/GuidanceComplianceRegulatoryInf
`
`product. Thus, once approved and launched,
`
`ormation/Guidances/UCM334743.pdf.
`
`INTAC IR products may enable physicians to
`
`(assessed July 3rd, 2013).
`
`ratios test/reference of Cmax, AUC0-t and
`
`simply switch from conventional to
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`AUC (area under the curve up to infinite
`
`80
`
`time) fell within the 80% to 125% range
`
`reformulated tamper-resistant products.
`
`Overall, the INTAC technology has
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`KASHIV1057
`IPR of Patent No. 9,492,393
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`B I O G R A P H I E S
`
`Dr. Johannes Bartholomäus studied Pharmaceutical Sciences at TU
`Braunschweig and finished his thesis in Pharmaceutical Technology in
`1988. He joined Grünenthal GmbH as Head of a Formulation Laboratory.
`From 1992 to 2008, he was heading Pharmaceutical Development and was
`an inventor of abuse-deterrent formulation technologies. In 2009, he
`started his own Pharmaceutical Development Consultancy. In addition, he
`is an invited lecturer for Industrial Pharmacy and Honorary Professor at
`TU Braunschweig.
`
`Dr. Sebastian Schwier, Associate Project Director in International
`Technical Alliance Management at Grünenthal GmbH, studied
`Pharmaceutical Sciences at the Westphalian Wilhelms University of
`Münster. He joined Grünenthal in 2008 as Laboratory Head within
`Pharmaceutical Development. Since 2012, he has been responsible as the
`CMC team leader for several INTAC® tamper-resistant formulation
`development projects.
`
`Martin Brett, Scientific Director in the Department of Pharmacokinetics
`at Grünenthal GmbH, studied Chemistry at Oxford University. He spent 15
`years in the pharmaceutical industry and a further 10 years in contract
`research, with interests mainly in bioanalytical methodologies and
`pharmacokinetic evaluation of clinical studies. He joined Grünenthal GmbH
`in 2005 responsible for the clinical pharmacokinetic team, and has
`supported the INTAC® project as the PK representative.
`
`Dr. Hans-Jürgen Stahlberg, International Clinical Lead and Director in
`the Department of Clinical Pharmacology at Grünenthal GmbH, has
`extensive experience in Pharmacokinetics (PK) and has published in peer
`reviewed journals on PK of analgesics and antibiotics. He holds a
`Certificate in Pharmaceutical Medicine from the University at Basle,
`Switzerland. His current focus lies on the clinical development of INTAC®
`tamper-resistant opioid formulations.
`
`Dr. Eric Galia, Project Director in International Technical Alliance
`Management at Grünenthal GmbH, studied Pharmaceutical Sciences at the
`University of Frankfurt. After various positions in the pharmaceutical
`industry, he joined Grünenthal GmbH in 2005. Since 2008, he has been
`involved in the development and project management of the INTAC®
`tamper-resistant formulation technology platform.
`
`Dr. Kai Strothmann, Senior Director Strategic Marketing & Portfolio
`Development at Grünenthal GmbH, studied Pharmaceutical Sciences and
`earned his PhD in Pharmacology at the University of Münster. After 10+
`years of diversified business experience in the healthcare industry across a
`broad range of functions and therapeutic areas, he joined Grünenthal
`GmbH in 2011 and takes care of marketing and life cycle management of
`the INTAC® tamper-resistant formulation technology.
`
`4. Butler SF, Cassidy TA, Chilcoat H et al. Abuse
`
`rates and routes of administration of
`
`reformulated extended-release oxycodone:
`
`initial findings from a sentinel surveillance
`
`sample of individuals assessed for substance
`
`abuse treatment. J Pain. 2012;14: 351-358.
`
`5. Endo Health Solutions Inc, Press Release. Nov.
`
`13, 2012. http://phx.corporate-
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`ir.net/phoenix.zhtml?c=123046&p=irol-
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`newsArticle_print&ID=1758228&highlight=.
`
`(assessed July 3rd, 2013).
`
`6. FDA News Release. April 16, 2013.
`
`http://www.fda.gov/NewsEvents/Newsroom/Pr
`
`essAnnouncements/ucm348252.htm. (assessed
`
`July 3rd, 2013).
`
`7. Throckmorton DC. The science of abuse-
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`deterrence - progress toward creating safer
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`opioids. FDA Voice. April 16, 2013.
`
`http://blogs.fda.gov/fdavoice/index.php/2013/0
`
`4/the-science-of-abuse-deterrence-progress-
`
`toward-creating-safer-opioids/. (assessed July
`
`3rd, 2013).
`
`8. Cassidy T. Impact of tamper resistant opioid
`
`formulations: findings from NAVIPPRO.
`
`http://www.navippro.com/uploadedFiles/Tamp
`
`erResistant.pdf. (assessed July 3rd, 2013).
`
`9. Bartholomaeus JH, Arkenau-Marić E, Galia E.
`
`Opioid extended-release tablets with improved
`
`tamper-resistant properties. Expert Opinion on
`
`Drug Delivery. 2012;9(8):879-891.
`
`10. Bartholomaeus JH, Ashworth JB, Stahlberg
`
`HJ, Galia E, Strothmann K. Innovative
`
`formulation technology protecting intended
`
`drug action. Drug Development & Delivery.
`
`2012;12(8): 69-75.
`
`11. Stahlberg HJ, Brett M, Ossig J, Schwier S,
`
`Philipp A. Bridging from conventional
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`marketed immediate release formulations to
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`new tamper resistant alternatives. J Pain.
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`2013;14(4, Suppl 1):S70.
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`KASHIV1057
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