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Pain Therapeutics Summit
October 3-4, 2012
San Jose CA
TAMPERABILITY/EXTRACTABILITY
OF PRESCRIPTION DRUGS
Robert P. Bianchi
Prescription Drug Research Center - Fairfax, VA
BACKGROUND
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Prescription drug abuse is the fastest rising category of
drug abuse in the US, second only to cannabis and
synthetic cannabinoids (ONDCP – Drug Control Strategy
2011).
Emergency department visits resulting from non-medical
use of prescription analgesics increased 98.4 percent
between 2004 and 2009 (NIDA 2011).
Seven of the ten substances most abused by high school
seniors are legal drugs used non-medically. 2009,
Monitoring the Future
According to DEA, 17 of the top 25 drugs most often
examined by forensic laboratories in 2011, are available as
prescription drugs. (DEA, NFLIS, 2011 mid year report)
BACKGROUND
An estimated (5%) 10.5 million Americans reported
past year use of prescription drugs for nonmedical purposes. (National Survey on Drug Use
and Health, 2008).
 Nearly 7 percent of youth between the ages of 12
and 17 (1.7 million) have used such drugs which
include pain relievers, sedatives, tranquilizers
or stimulants, for non-medical purposes at some
point.
(National Survey on Drug Use and Health,2008)
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BACKGROUND
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What caused this phenomenon?
Prescription drugs do not fall under the
clandestine cloud of illegal drugs such as heroin,
ecstasy or methamphetamine
 Prescription drugs are more available due to the
development of new products and increased sales
 Drugs are FDA approved
 Friends and family use them
 Drugs are frequently obtained free of cost
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TYPES OF ABUSERS*
Health care professionals – easy access, educated
 Hard core opioid addicts – prefers heroin to Rx
 Casual – low tolerance, alcohol & marijuana
 Polydrug/Rave – uses anything available
 Patient abuser – scammer, doctor shopper
 SR Hard core Rx – converts to IR
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* Sidney H. Schnoll, MD, PhD
DIVERSION METHODS
 Doctor
shopping or other prescription fraud
 Illegal online pharmacies
 Theft and burglary (from residences,
pharmacies, etc.)
 Stereotypical drug dealing (selling pills to
others)
 Receiving from friends or family, often for little
or no cost
 Over prescribing (negligent or intentional over
prescribing by physicians)
INFORMATION SOURCES
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Most abusers do not have technical training and get
their information on abuse and extraction methods from
friends, publications or the Internet
Web sites
 http://www.courtinfo.ca.gov/opinions/revpub/A100018.DOC
 http://www.rhodium.ws/chemistry/
http://www.erowid.org/index.shtml
 http://www.totse.com/en/drugs/speedy_drugs/166004.html
 http://www.the-hive.ws/forum/forums.pl
 http://nepenthes.lycaeum.org/Drugs/DXM/extract.html
 http://www.erowid.org/chemicals/dxm/faq/dxm_chemistry.shtml
(good detail)
 http://www.bluelight.ru/
News group:
 Alt.drugs, Alt.drugs.hard, Rec.drugs, Lycaeum
Amazon.com
INDUSTRY RESPONSE
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Development of abuse resistant delivery systems
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Benefit to industry
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Reformulation - Oxycontin
Oros® – osmotic pump (POLYOX)
Encapsulated pellets
Addition of antagonists
Capsules within capsules
Rel-Ease™ - Ionic complexes
Packaging
Reservoir transdermal patch
Pro-drugs
ADPREM
Dose counting devices
Enhanced corporate image
Fewer litigation actions
Increased market share
 Lower schedule ? – more doctors will prescribe
 Perceived as safer leading to increased prescriptions
Patient/Public Benefit
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Reduced abuse and subsequent health care costs
SCHEDULING
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The DEA in concert with FDA has been delegated the
authority to add or transfer substances between
schedules if the substance has a potential for abuse and
meets the criteria for a particular schedule or remove
them completely from scheduling
Scheduling based on eight factor analysis
(combined to major three issues)
Potential for abuse and actual pattern of abuse and
dependence (combines Factors 1, 4, 5, and 7). Ease
of tampering or extracting.
Chemistry and pharmacological effect (combines
Factors 3 and 2), including whether the substance is an
immediate precursor of a controlled substance (Factor 8)
Public health risks (Factor 6)
EIGHT FACTORS
The 8 factors are specified in the Controlled Substance Act (CSA) as:
(1) The drug/substance actual or relative potential for abuse
(2) Scientific evidence of the drug/substance pharmacological effect, if known
(3) The state of current scientific knowledge regarding the drug/substance
(4) The drug/substance history and current pattern of abuse
(5) The scope, duration, and significance of abuse
(6) What, if any, risk there is to the public health
(7) The drug/substance psychic or physiological dependence liability
(8) Whether the drug/substance is an immediate precursor of a substance already controlled
under this subchapter
ABUSE METHODS
 Physical
– oral, snorting, smoking
 Multiple
doses
 Heating patches
 Crushing
 Chewing
 Grinding – hammer, coffee grinder, kitchen utensils
 Removal of barrier – cut patch
 Extraction
 Solvent
–oral, nasal, smoking, IV
extraction to remove excipients and/or
concentrate active ingredient
DEFINITIONS
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Tampering – physical manipulation
Crushing
 Physical separation components (beads, layers,
gel)
 Heating, freezing, crisping, microwaving
 Extractability – chemical manipulation of a
product to remove, concentrate and/or purify the
active ingredient performed using commonly
available equipment and chemicals
 Procedures may be used individually or in
combination – crushing is frequently the first step
in solvent extractions
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EXTRACTION EXPERIMENTS
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Standardized laboratory extractions must be
developed for each type of dosage form, e.g.
tablets, capsules, patches, liquids, IR, SR using
solvents & equipment commonly available.
All experiments must be conducted at least in
triplicate to provide statistical validity. Controls
and a comparator must included.
IN-VITRO EXPERIMENTS
aka KITCHEN CHEMISTRY
Every product is different; therefore each
requires a unique set of experiments to
assess tamperability.
 Sponsor knows product’s vulnerabilities and
should develop experiments in concert with
abuse experts based on product knowledge
and current abuse methods of similar
products using commonly available
chemicals and equipment.
 Consider testing all dosage strengths
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IN-VITRO EXPERIMENTS
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Develop written protocols that produce
statistically valid, reproducible results.
 Include related comparator product
 Include controls
 Include quality assurance procedures
 Take photographs to illustrate results
 Use graphs and charts to illustrate data
SOLVENT EXTRACTION
EXPERIMENTS
 Information
I can share was presented at the
American Pain Society annual meeting.
Janssen sponsored study to compare the
extractability of fentanyl from reservoir and
matrix patches. All extractions were performed
by NMS Laboratories using chemicals and
equipment available to the general public.
Identification and purity of extracts confirmed
by GC/MS/MS
FENTANYL
TRANSDERMAL SYSTEMS
The DURAGESIC reservoir patch is a formfill-seal design that contains a suspension of
fentanyl base in a water/ethanol and
hydroxyethyl cellulose solution.
 The matrix patch is a drug-in-adhesive
formulation that contains fentanyl base
dissolved in an adhesive.
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FENTANYL
TRANSDERMAL SYSTEMS
DURAGESIC®
Reservoir
Backing Layer
Fentanyl
Generic
Fentanyl Base in Gel
Backing Layer
Adhesive and Fentanyl Base
Rate Controlling Membrane
Skin
Adhesive
Skin
FENTANYL
TRANSDERMAL SYSTEMS
Products extracted
 Duragesic® 10 mg/patch – 100μg/hr
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Matrix
18.4mg/patch -100µg/hr
Solvents used
Water
 Vodka (40% ethanol)
 Bacardi 151 rum
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Rubbing alcohol (IPA)
 Vinegar
 Methyl alcohol
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EXTRACTION TECHNIQUES
Protective layers removed and intact
patches subjected to extraction
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“Room temperature Soak” (party punch): each
patch left undisturbed in 500 ml of each solvent
at RT.
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“Elevated Temperature Soak”: each patch
soaked in 500 ml of solvent at boiling point.
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“3 Hour Percolation”: each patch percolated
with 750 ml of each solvent.
ROOM TEMPERATURE SOAK
Methanol
Rum
IPA
100
Vodka
% yield
75
Matrix
50
25
Vinegar
Water
Duragesic®
0
0
50
100
minutes
150
200
IN-VITRO EXPERIMENTS
 Particle
size reduction is generally the first step.
 Experiments should be attempted at RT and ET as
well as after physical manipulation (heating,
freezing, microwaving, crisping)
 Use a variety of available manual and electric tools
 Set practical time limits (Egalet study- 80% of
subjects would spend 3-10 minutes tampering)
 Smallest particle size generally produces the most
desirable result.
SOLVENT EXTRACTION
EXPERIMENTS
Solvents
of different pH and polarity
Soaked and stirred
RT and elevated temperature (ET)
Ground and intact
Percolated
Single solvent (ingestible e.g. alcohol,
water - non-ingestible e.g. paint thinner,
acetone)
Multiple solvents - aqueous /pH
adjustments & immiscible solvents
EXTRACTION EXPERIMENTS
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All modes of abuse must be considered
 Oral – the most commonly encountered
 Nasal – crushing followed by snorting
 Smoking – crushing/extracting  IV – hard core abusers requiring
immediate most intense result
INJECTABILITY
Photos by permission, Egalet, Copenhagen DK, 2010.
CRISPING
Photos by permission, Egalet, Copenhagen, DK 2010.
EXTRACTABILITY RATING
Neither the DEA nor FDA have objective
criteria to measure/evaluate extractability.
Ideally, a rating system should be developed that
would result in a quantitative score that regulators
and industry officials could use to determine the
relative extractability of any pharmaceutical product.
In February 2012, Dr. Douglas Throckmorton, deputy
director of CDER, stated that the FDA will be
releasing industry guidance on tamper-resistant
formulations by the end of the 2012.
EXTRACTABILITY RATING
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Objective metrics must be established Number of steps required
 Amount of equipment and chemicals required
 Amount of time expended
 Percent recovery
 Other active & inactive ingredients recovered
 Physical characteristics of extract – viscosity,
color, odor, syringability
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EXTRACTION EXPERIMENTS
 Although
pharmaceutical companies and drug
delivery development companies have their own
laboratories, the objectivity of an independent
laboratory is sought in addition to or instead of
in house experiments. FDA guidance to industry
recommends that in vitro experiments be
conducted by an independent laboratory that is
blinded to the fullest extent possible (after the
May 2008 advisory committee meeting, FDA
advised Purdue to utilize an independent
laboratory to conduct in-vitro experiments of
reformulated OxyContin).
Summary
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No objective measure exists to measure
Tamperability/extractability
Each product/system requires unique
experiments designed to address vunerabilities
Use independent laboratory & abuse experts
Consider all modes of abuse & all strengths
Include photographs, graphs & charts where
appropriate
No product has been proven to be tamper
proof
Thank you
Robert P. Bianchi
Vice-President and Chief
of Scientific and Technical affairs
Prescription Drug Research Center
134 N. LaSalle Street
Chicago, IL 60602
312-726-8620 - Office
571-233-4780 – Cell
[email protected]
[email protected]