Pharmaceutical Development of Novel, Abuse Deterrent Extended Release Dosage Forms
of the Multimodal Analgesic, Levorphanol
N.
1
Babul ,
V.M.
1TheraQuest
2
Young ,
M.
2
Bakhshaee ,
A.
2
McNaughton ,
Biosciences Inc., Blue Bell, PA, USA,
ABSTRACT
METHODS (continued)
Background and aims: Levorphanol is an analgesic with multiple mechanisms of action. This study was
designed to develop and evaluate abuse deterrent extended-release (ER) dosage-forms of levorphanol ER
which resist tampering
•Abuse deterrence testing methods included:
Methods: Approximately 20 formulations of levorphanol were tested to identify stable, ER dosage forms with
robust in-vitro dissolution, tamper-resistant profile and a release rate consistent with once-a-day dosing.
Generally recognized as safe (GRAS) base excipients, comprising water insoluble thermo-softening waxes were
chosen to impart an ER profile. The contribution of several release-rate modifiers, thixotropes and fractionated
coconut oil were also evaluated. An HPLC method was developed for assay of levorphanol. Methodologies were
developed to evaluate tamper resistance. Dosage forms were subjected to tampering, including crushing,
grinding, dissolving, melting, needle aspiration, filtration and solvent extraction in order to determine their tamperresistance relative to commercially available abusable products
2Encap
H.D.
1
Kao ,
S.
Drug Delivery, Livingston, UK
3. Extraction into water: (i) crush with a mortar and pestle; (ii) grind contents with 5 mL of water for 5 min;
(iii) filter the resulting suspension a 0.45 micron filter into a flask; (iv) dilute to 10 mL with water; (v)
quantify active drug by HPLC.
Conclusions: Oral dosage-forms of levorphanol comprising a high melting-point wax, a release-rate modifier, a
thixotrope and fractionated coconut oil provide robust extended-release, tamper-resistant profile. Levorphanol
ER dosage-forms have been subjected to Phase I bioavailability evaluation.
6. Application of heat: (i) crush with a mortar and pestle and grind contents; (ii) heat contents on a hot
plate until melted and determine “melting point”; (iii) aspirate melted contents into 5 mL syringe fitted
with a 1.2 mm luer-lock needle; (iv) expel any aspirated contents from syringe via needle.
Dosage forms that deliver drug to the GI tract over an extended period have variously been referred to as
“sustained release”, “controlled release”, “long acting”, “modified release” and “extended release” formulations. An
extended release (ER) dosage form of levorphanol is presently in development. ER analgesics are now the
standard of care in chronic pain and they have the potential to provide fewer interruptions in sleep, improved
compliance, enhanced quality of life outcomes, and increased control over the management of pain. In addition,
ER analgesics can provide more constant plasma concentrations and clinical effects, less frequent peak to trough
fluctuations and fewer side effects.
Unfortunately, opioid analgesics can also be used for non-medical purposes. Figure 1 shows the number of new
illicit users of psychoactive substances in the U.S. each year. Opioid abuse may involve the intact dosage form or
a tampered dosage form. Tampering of an ER opioid has the potential to rapidly deliver a large dose in immediate
release form and therefore produce opioid toxicity.
OBJECTIVES
The objective of this study was to develop and evaluate abuse deterrent extended-release (ER) dosage-forms of
levorphanol which resist tampering.
METHODS
• Approximately 25 binary mixtures of base excipients and levorphanol were held in a stability chamber set at 40ºC/
75%RH for one month and then examined by HPLC for degradants and impurities.
• Cleaning, dissolution and analytical methods were developed for levorphanol ER dosage form evaluation.
• The dosage forms were prepared using a variety of GRAS (Generally Recognized As Safe) base excipients.
• Methodologies were developed and adapted to evaluate tamper resistance in the setting of drug abuse.
• The potential for abuse of the levorphanol formulations were tested and modified to incorporate significant abuse
resistance.
• Approximately 20 experimental formulations of levorphanol utilizing four different base excipients were developed
to provide an abuse deterrent ER profile suitable for once-a-day dosing.
• The routes of administration of a levorphanol ER dosage form in the setting of abuse may include oral, IV,
intranasal and inhalation after crushing, melting, solvent extraction, filtration and syringe aspiration.
• Dosage forms were therefore subjected to tampering, including crushing, grinding, dissolution, melting, needle
aspiration, filtration and solvent extraction in order to determine the degree of tamper resistance relative to other
abusable products..
(> 2 million new illicit U.S. pain users per year)
2. Extraction with alcohol from crushed dosage unit: (i) crush intact dosage form with a single crush of a
spatula; (ii) place crushed dosage form in 18 mL of 0.1N HCl in a 60 mL amber bottle and shake at 240
rpm in an orbital shaker for 30 min; (iii) continue the test described for the intact dosage form above.
4. Dry sieving efficiency: (i) freeze the intact dosage unit in a domestic freezer for 24 hr; (ii) remove the
shell (if capsule) with a scalpel; (iii) grind with a mortar and pestle for 1 min; (iv) sieve through a 600
micron sieve; (v) collect and weigh sieved content.
Levorphanol is a broad spectrum analgesic which, unlike morphine and many commonly used opioid analgesics,
combines multiple important pain relieving mechanisms, including opioid agonism, monoaminergic reuptake
inhibition and NMDA antagonism. It is being developed as a once-a-day extended release, abuse deterrent
dosage form for the management of chronic pain.
Fig. 1: Illicit Use of Prescription Pain Drugs
1. Extraction with alcohol from the intact dosage unit: (i) place whole dosage unit in 18 mL of 0.1N HCl in
a 60 mL amber bottle and shake at 240 rpm in an orbital shaker for 30 min; (ii) swirl and remove a 1
mL sample (T0); (iii) add 12 mL of ethanol (95%); (iv) place solution bottle back in the orbital shaker at
240 rpm; (v) take 1 mL samples after 10, 20, 30, 40, 60 and 180 min; (vi) assay for levorphanol release
over time.
Results: Four final abuse-deterrent levorphanol ER dosage forms with robust in vitro dissolution, tamperresistant profiles and a release rate consistent with once-a-day dosing were developed. The dosage forms were
liquid-filled into small (size 2) hard-shell capsules. Waxes with melting-points of >50°C were selected. HPMC
was chosen as the release-rate modifier and fumed silicon dioxide as the thixotrope. Fractionated coconut oil
reduced brittleness. Each excipient appeared to independently contribute to the tamper resistant properties of
the dosage form.
INTRODUCTION
2
Brown
5. Extraction into acid: (i) crush intact dosage form with a mortar and pestle; (ii) heat contents to boiling in
5 mL of 8% acetic acid; (iii) filter the resulting suspension through a 0.45 micron filter into a flask; (iv)
dilute to 10 mL with water; (v) quantify active drug by HPLC.
2008 NSDUH Survey, Substance Abuse and Mental Health Services Administration
Fig. 2. Intact Dosage Form: Resistance to Alcohol
Levorphanol ER (A, B, C, D) vs. OxyContin ® 80 mg Tablets*
•Except where otherwise specified, the dissolution was conducted using USP Paddle Method (Apparatus II) in
600 mL of Simulated Intestinal Fluid (SIF) USP, pH6.8 without the inclusion of enzyme. Levorphanol was
measured by HPLC.
RESULTS
•Four formulations with varying dissolution profiles and combination of base excipients were found to meet
all required criteria.
•Clinical trial batches of the final four formulations were manufactured under GMP conditions and placed on
stability testing at 25ºC/60%RH, 35ºC/65%RH and 40°C/75% RH for up to 12 months
•All four GMP levorphanol ER formulations demonstrated a high level of abuse and tamper resistance under
a variety of in vitro conditions described above.
•The tamper efficiency across the 4 levorphanol ER prototypes versus OxyContin® 80 mg tablets (previously
marketed controlled release oxycodone product, FDA Product Application # N020553), was:
4 to 27% versus 82% in water after crushing and grinding, followed by filtration (Test 3)
5 to 17% versus 67% after freezing, crushing and grinding, followed by sieving (Test 4)
2 to 34% versus 90% after crushing and grinding, followed by boiling in acetic acid and filtration (Test
5)
•Figure 2 show the relative alcohol resistance of intact dosage forms of levorphanol ER (A, B, C, D) versus
the OxyContin ® 80 mg tablets described above (Test 1). Each dosage form was placed in 0.1N HCl,
agitated at 240 rpm in an orbital shaker for 30 min, followed by addition of 95% ethanol and continued
agitation in the orbital shaker. Drug samples were obtained at 0 (upon addition of ethanol), at 10, 20, 30,
40, 60 and 180 min.
•Figure 3 shows the relative abuse resistance of tampered dosage forms of levorphanol ER (A, B, C, D)
versus the OxyContin ® 80 mg tablets described above (Test 2 to 30 min). Each dosage form was crushed
with a mortar and pestle, ground and vigorously mixed in 0.1N HCl for 30 min (Figure 3, left panel), then
further vigorously mixed in 95% ethanol for 30 additional min (Figure 3, right panel),
Fig 3. Tampered Dosage Form: Resistance to Alcohol and Acid
Levorphanol ER (A, B, C, D) vs. OxyContin ® 80 mg Tablets*
CONCLUSIONS
• A number of strategies were evaluated to develop proprietary abuse deterrent, extended release dosage
forms of levorphanol, a broad spectrum analgesic which combines multiple pain relieving mechanisms,
including opioid agonism, monoaminergic reuptake inhibition and NMDA antagonism.
• The formulations underwent extensive compatibility, in vitro abuse deterrence and dissolution stability
testing. Four promising formulations were selected for GMP manufacture and Phase I bioavailability
evaluation.
• Abuse deterrent formulations of extended release levorphanol have the potential to reduce toxicity from
intentional or inadvertent tampering. Such formulations may also deter drug abuse and the diversion of
the product into the illicit market.
*OxyContin® 80 mg tablets tested in this study (FDA Product Application # N020553) were
marketed until 2010 when they were replaced by a new formulation which makes the tablet
more difficult to tamper.
CORRESPONDING AUTHOR:
Najib Babul, PharmD
TheraQuest Biosciences, Inc.
P.O. Box 1266, Blue Bell, PA 19422-0409, USA