T2141
INTAC : A Novel Formulation Platform to Protect Intended Drug Action.
®
L. Barnscheid , K. Wening , E. Galia , J. Bartholomäus
1
1
1
2
1 Grünenthal GmbH, Aachen, Germany
2 Pharmakreativ Consulting, Aachen, Germany
Results and Discussion
100
Other
Inject
Inhale/Snort
Chew
Intended ROA
in %
80
Different formulation approaches have been suggested to overcome this
problem for extended release formulations, including the addition of
aversive agents (e.g. emetics, bittering agents) or the combination with
antagonists. All these approaches share the risk of potentially harming
patients taking the product as directed.
60
INTAC® tablets withstood breaking forces of above 500 N without
rupture, thereby hindering pulverization by application of mechanical force, e.g. by using spoons, pill-crusher, or hammer strike. In a
Example 1: Use of 2 spoons for manipulation
40
0
Oxycodone
Morphine
Oxymorphone
Fig. 1 Analysis of self-report data collected from individuals entering substance abuse treatment in
2009 (adapted from Butler et al, Harm Reduction Journal 2011)1
Materials and Methods
% released
20
direct comparison with a conventional ER tablet, INTAC® tablets
showed their superior performance after the mentioned manipulation attempts. In an in-vitro test it could be demonstrated that the
Example 2: Pill crusher in nursing home environments
Example 3: Use of 500 g hammer
100
100
100
80
80
80
Two spoons – conventional
ER tablet
60
Two spoons – INTAC™ tablet
Intact tablet with
intended release
40
Pill crusher – conventional
ER tablet
60
Pill crusher – INTAC™ tablet
Intact tablet with
intended release
40
0
0
0
4
6
8
10
12
14
0
2
4
6
8
10
12
Grünenthal, data on file
14
0
2
Fig. 4 Use of two common household
spoons for manipulation and comparison of dissolution profiles of manipulated tablets (n=3 ± SD)
4
6
8
10
12
14
Time (h)
Time (h)
Grünenthal, data on file
Grünenthal, data on file
By using a tablet press with a special design feeding system cut
rods were formed to standard shaped tablets, which finally were
film-coated (2).
Intact tablet with
intended release
40
20
Time (h)
1
Hammer – INTAC™ tablet
20
2
Hammer – conventional
ER tablet
60
20
0
Conceptional design
In a systematic approach different routes of tampering drug products
were evaluated in combination with potential approaches to prevent
such manipulations. 4 main categories of manipulation were identified
and paired with 10 approaches on abuse-deterrence. Potential risks
to the patient of those approaches as well as their functionality against
the 4 abuse categories were compared.
dissolution profiles after such manipulations varied less than 5%
from the non-manipulated reference (Fig.4-6).
% released
The misuse and abuse of opioid drug products is an increasing societal
problem of epidemic scale. This is especially the case for extended
release (ER) products as a high dose is accessible by manipulating a
single dosage form. Routes of abuse vary between individual drug
substances and drug products.
% released
Introduction
Fig. 6 Use of a standardized hammer
test simulating a 500 g hammer (pictures
only for illustration) for manipulation
and comparison of dissolution profiles of
manipulated tablets (n=3 ± SD)
Fig. 5 Use of professional pill crusher for
manipulation and comparison of
dissolution profiles of manipulated
tablets (n=3 ± SD)
2
Pairing technology with the relevant routes of abuse
Approach / Route
of abuse
Multiple doses,
swallowing intact
Chewing
Snorting
Injecting
Niacin dose trials
Emetic
30
Bittering agent
4
Dye
Capsaicin
Naloxone
Naltrexone (sequestered)
Gelling
Fig. 3 Process steps for manufacturing of Gruenenthal TRF Tablets
Hardness
Fig. 2 Approaches to prevent tampering of drug products and highlighted: TRF (Tamper
Resistant Formulation) approach of Gruenenthal, focusing on gelling and hardness
Based on the assessment a mechanical abuse-deterrence approach
was chosen aiming at the prevention of pulverization of the tablet.
Manufacturing
A powder mixture of the active compound, polyethylene oxide and hypromellose as controlled release agents, polyethylene glycole as plasticizer and vitamin E as anti-oxidant was blended and subsequently fed
into an extruder. Hot Melt Extrusion was performed using a twin screw
extruder with a single-bore die at temperatures above the softening
point of the mixture. The obtained strand was cooled and cut into rods
containing the single dose (Fig. 3).
®
Characterization
Resistance to crushing
Resistance to crushing was measured using a conventional breaking
force tester having an extended measuring range up to 1000 N.
Dissolution
Dissolution testing was performed using an USP 2 apparatus with
photometric quantification. The medium was phosphate buffer
(pH 4.5) at 37°C; paddle speed was adjusted to 50 rpm.
Extraction
The tablet was shaken in the respective solvent. Content was determined after 15 min and 60 min using a validated HPLC method. Tablets
were analyzed intact and after manipulation with a professional pill
crusher.
Intact tablet (40 mg)
15 minutes
1 hour
Mean amount of drug extracted (% LC)
3
Pro-drug
Grünenthal's Tamper Resistant Formulation Technology INTAC
More experienced abusers tend to switch
from oral to non-oral use, eg. snorting or i.v.
injection. Trying to dissolve INTAC® tablets in
low amount of liquids results in the formation of a highly viscous gel (Fig. 8) that deters
from abuse by injection.
Range of drug extraction - "Kitchen Chemist"
20
10
The generation of a pulverized preparation
as a pre-requisite for snorting is hindered by
the mechanical properties of INTAC®.
0
30
Pill – crushed tablet (40 mg)
1 Butler et al, Abuse risks and routes of administration of different
prescription opioid compounds and formulations, Harm Reduction
Journal, 2011.
2 Bartholomäus, JH, Arkenau-Maric E, Galia E, Expert Opinion on
Drug Delivery Aug 2012, Vol. 9, No. 8: 879–891
10
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Gruenenthal developed an extended release formulation platform
requiring no aversive additives (INTAC®) which protects intended drug
action and raises hurdles against misuse and abuse. INTAC® tablets are
characterized by a superior resistance against pulverization by exhibiting a breaking strength of more than 500 N.
References
20
0
Conclusion
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Fig. 7 Drug extraction in various solvents of intact and manipulated INTAC® tablets (n=3 ± SD)
Extraction in different media was performed to simulate the various house-hold typical
solvents. The results of extraction trials are presented in Fig.7.
Fig. 8 Exemplary behavior of material used for INCTAC®
Tablets forming highly viscous gel after mixing with liquid
APPS Annual Meeting, Chicago 2012
E. Galia, Pharmaceutical Development,
Grünenthal GmbH, Zieglerstr. 6,
52078 Aachen, Germany
Tel.: +49-241-569 25 53, Fax: +49-241-569 19 27
Eric.Galia@Grunenthal.com
AAPS Annual Meeting, Chicago 2012