<p>Opioid addiction
has become a global epidemic and a national health crisis in recent years. In
2016, approximately 64,000 Americans under 50 years old were killed because of
opioid overdoses. The aim of developing an abuse deterrent opioid is to render
any form of manipulation that encourages abuse challenging and therefore,
non-profitable. With this goal, the Food and Drug Administration (FDA) is
extensively supporting research into the development of abuse deterrent
technologies and prioritizing their production as a public health
necessity. Abuse deterrent approaches include but are not limited to the
following: (1) using a physical
barrier (e.g., Polyethylene oxide PEO) that basically limit the release
of the drugs in the blood or the digestive tract and prevent mechanical
alteration of the drugs by crushing, grating, grinding, chewing etc, (2) using
chemical barriers that employ gelling agents that prevent the aqueous or organic
extraction of the drugs, and (3) combining
the drug with an antagonist that blocks
the post-abuse euphoria.</p>
<p>PEO is a popular
polymer used as a matrix in these complex opioid products. The polymer is
responsible for the abuse deterrent properties as well as extended release
behavior of opioid drugs. PEO hinders the extraction of Opioid drugs from Abuse
Deterrent Formulations (ADF), makes it challenging to be injected, and resists
mechanical stress and pulverization when crushed. PEO can be subjected to thermal processing such as thermal curing,
compression molding, melt extrusion, and injection molding owing to its
thermoplasticity.</p>
<p>Assessment of the
impact of using various manufacturing processes to develop ADFs and the effect
of using various grades of this polymer is essential to improve upon the next
generation of ADFs. There are three main
categories of premarket studies: Category 1 – laboratory based (in-vitro
manipulations and drug extractions), category 2 – pharmacokinetic and category
3 –clinical. These studies are required by the FDA to demonstrate that a given
formulation exhibit abuse deterrent properties before a drug product is
released to the market. In vitro laboratory based manipulation and
extraction studies which are used to assess AD properties of these
products are challenging, but essential for product development and
generic abuse deterrent product approvals. It is important to realize
that there is a great correlation between the laboratory based in vitro
manipulation and extraction studies and the expectations of potential abuse and
misuse of opioid drugs. The ability of these studies to mimic the manipulation
techniques applied by abusers to defeat the abuse deterrent properties of a given
formulation optimizes predictions on post-market abuse and misuse potential of
ADFs. These studies should also correlate well with <i>in-vivo</i> studies since there is a direct correlation with the
concentration (mg/mL in water) and the “high” obtained by an abuser. </p>
<p>This research aimed
to conduct laboratory based in vitro manipulation and extraction studies to investigate
failure modes of PEO-based
prescription opioids and Promethazine Hydrochloride PMZ HCl tablets. It
highlighted the formulation
components and the manufacturing parameters that might affect the dose dumping of
Active Pharmaceutical Ingredients (APIs). Furthermore, this research identified
model compounds that can be used as surrogates for Oxycodone and the best
experimental setup that can be used to conduct smoking simulation experiments.
Moreover, it provided an overview of the societal impacts of the opioid crisis
in the state of Indiana.</p>
<p>Investigations of the
failure modes of the PEO-based prescription opioids and PMZ HCL tablets showed
that physical manipulation techniques via chopping or grinding are much more
effective in the destruction of the PEO matrix than thermal manipulation via
the application of heat thus promoting the fast release. The factor with the most
significant effect on the failure modes of PMZ HCL tablets was the application
of physical manipulation, while the one with the lowest impact was the polymer
grade. Moreover, producing PEO-based matrix tablets
via Direct Compression DC significantly affected dose dumping behavior of the
API from the drug products. The production of the PEO-based matrix tablets via DC
was found to be favored over the usage of the melt extrusion method and molding
techniques. It was clear that DC kept the integrity of the polymer, allowed for
slow and controlled release fashion of the API, and rendered the extraction
process relatively hard compared to the Hot Melt Extrusion HME and Molding
techniques.</p>
<p>Furthermore, the
release profile of the investigated PMZ HCL products consisted of various phases
of polymer swelling and API release. Thermal manipulations via the application
of heat were found to accelerate the dose dumping
behavior (90% release) of the APIs from the compressed, extruded, and molded
PEO-based matrix formulations similarly. On the other hand, heating was
much more effective in the extraction of APIs than chopping or grinding thus
promoting the ability to<b> </b>draw a
solution containing the API into a syringe for injection relatively easy and
facilitate higher % API recovery.</p>
<p>Among the formulation components that might have an
impact on the AD properties of the PEO-based drug products are; the choice of
the antioxidant, the use of complexing agents, chelating agents, and
plasticizers. On the other hand, manufacturing process variables that might
have a critical impact on AD properties of the PEO-based drug products include
but are not limited to; processing temperature compared to the melting point of
the polymer and time of exposure</p>
<p>PMZ HCl was used
as a model drug for Oxycodone in dissolution and extractability studies, while
Caffeine and L-Nicotine were used as model drugs in smoking simulation
experiments. The combination of the propane torch and Kugelrohr apparatus mimic
the real-world scenario for smoking Opioids; however, this experimental setup
caused thermal degradation rather than vaporization of some model drugs.</p>
<p>According to the National
Center for Health Statistics; a statistically significant increase in drug
overdose death rates was reported in 2016 in the state of Indiana among other
states. The number of deaths related to opioid pain relievers increased by 3732
folds in 2017 compared to the number of deaths in 2014. Moreover, Males were
more affected by the opioid crisis than females. On the other hand, the age
group 25-44 years, and white people were the most affected by the opioid crisis
in Indiana. </p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/9107903 |
| Date | 15 August 2019 |
| Creators | Salma Salem (7042751) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/FAILURE_MODES_OF_PEO_BASED_ABUSE_DETERRENT_OPIOIDS_AND_PROMETHAZINE_HYDROCHLORIDE_TABLETS/9107903 |
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